3-Quinolin-2(1h)-ylideneindolin-2-one derivative

ABSTRACT

There is provided medicaments, particularly a vascular endothelial growth factor (VEGF) inhibitor which is useful as a therapeutic drug for solid tumors, diabetic retinopathy and the like diseases in which angiogenesis is taking a role. That is, since a novel 3-quinolin-2(1H)-ylideneindolin-2-one derivative or a salt thereof has good VEGF inhibitory action, angiogenesis inhibitory action and anti-tumor action, it is useful as ideal VEGF inhibitor, angiogenesis inhibitor and anti-tumor agent.

TECHNICAL FIELD

This invention relates to medicaments, particularly a vascularendothelial growth factor (VEGF) inhibitor which is useful as atherapeutic drug for diseases in which angiogenesis is taking a role,such as cancers, diabetic retinopathy and the like.

BACKGROUND OF THE INVENTION

It is known that several diseases accompany pathological angiogenesisclosely related to their symptoms and causes. Typical disease among themis cancer, particularly a solid tumor, and it is necessary that a bloodvessel newly formed from an already existing blood vessel elongates andreaches a tumor tissue, for the tumor tissue to grow to a diameter ofexceeding 1 to 2 mm (J. Natl. Cancer Inst., 82, 4 (1990))), and growthof the tumor tissue is explosively accelerated once the blood vesselreaches the tumor tissue. Also, a pathological angiogenesis accompaniesin the retina in the case of diabetic retinopathy and frequently causesthe loss of eyesight. In addition, a pathological angiogenesis isaccompanied also by diseases such as rheumatoid arthritis, psoriasis,hemangioma, scleroderma, neovascular glaucoma and the like, and it isbecoming one of the main symptoms (N. Engl. J. Med., 320, 1211 (1989)).Accordingly, there is a possibility that a substance which inhibitsangiogenesis can be applied to the treatment of solid tumors and theaforementioned diseases.

Vascular endothelial cells are cells which form innermost layer of ablood vessel. Angiogenesis is carried out by the proliferation ofendothelial cells triggered by a growth factor or a physiologicallyactive substance or by undergoing a stimulus such as a physical injuryor the like. Though there are several growth factors that directly orindirectly stimulate growth of vascular endothelial cells, a vascularendothelial growth factor (VEGF) is known as a factor which isdistinguished from other growth factors in terms that it acts uponvascular endothelial cells markedly specifically. That is, it has beenreported that the VEGF receptors are vascular endothelium-selective,because they are expressed in very limited cells other than the vascularendothelial cells (J. Clin. Invest., 89, 244-253 (1992)).

There are the following reports which suggest relationship between VEGFand cancers. Many cancer cells secrete VEGF (Biochem. Biophys. Res.Commun., 194, 1234 (1993)). A cancer tissue and newly formed bloodvessel in its periphery are strongly stained when a cancer tissuesection is stained with an anti-VEGF antibody (J. Exp. Med., 174, 1275(1991), Cancer Res., 53, 4727 (1993)). Growth of a transplanted canceris inhibited in mice in which one of the VEGF receptors is geneticallyinactivated (Nature, 367, 576 (1994)). An anti-VEGF neutralizingantibody shows an anti-tumor activity in tumor bearing mice (Nature,362, 841 (1993), Biochem. Biophys. Res. Commun., 194, 1234 (1993)).Based on the above facts, it is considered that the VEGF secreted bycancer cells takes a central role in the tumor angiogenesis. Inaddition, since it is known that VEGF is also concerned in theacceleration of vascular permeability, this is considered to be one ofthe factors which cause malignant ascites and pleural effusionproduction.

Regarding the receptor of VEGF, two receptors Flt-1 and KDR/Flk-1 areknown in the case of human (FASEB J., 13, 9-22 (1999)). From a result ofthe disruption of these two genes, it has been shown that Flt-1 isconcerned in the normal differentiation and morphogenesis of endothelialcells, and Flk-1 in the formation and growth of endothelial cells(Nature, 376, 66-70 (1995), Nature, 376, 62-66 (1995), Nihon YakurigakuZasshi (Japanese Journal of Pharmacology), 107, 119-131 (1996)). It isconsidered that VEGF binds to the Flk-1 receptor and accelerates growthof vascular endothelial cells via a tyrosine kinase-mediated signaltransduction mechanism (Proc. Natl. Acad. Sci. USA, 88, 9026-9030(1991)). It is shown also that VEGF has a direct in vitro angiogenesisinducing activity upon endothelial cells (J. Cell. Physiol., 149, 50-59(1991)).

Accordingly, it is expected that a VEGF inhibitor capable of inhibitingbinding of VEGF with a VEGF receptor (particularly Flk-1) or inhibitingthe VEGF signal transduction will inhibit angiogenesis and malignantascites production and the like and therefore will be useful for thetreatment of cancers, particularly solid tumors.

As the VEGF inhibitors, an anti-VEGF human monoclonal antibody(JP-A-9-316099) and some polypeptides (JP-A-9-255700, JP-A-9-154588)have been reported. Recently, low molecular weight compounds such asSU6668 (Cancer Res., 60, 4152-4160 (2000)), PTK787/ZK222584 (CancerRes., 60, 2178-2189 (2000)) shown below which can be orally administeredand show VEGF inhibitory action have been reported.

In addition, quinazoline-substituted oxindol derivatives (WO 97/42187and WO 99/10349) and pyrrolotriazine-substituted indolin-2-onederivatives (WO 00/71129) have been disclosed as useful compounds as atyrosine kinase inhibitor and an angiogenesis inhibitor. However, thereis no disclosure on their concrete pharmacological data.

Regarding the 3-quinolin-2(1H)-ylideneindolin-2-one derivative on theother hand, there are reports on the synthesis method of3-quinolin-2(1H)-ylideneindolin-2-one as the compound (I′) of theinvention which will be described later wherein m and n are both 0 (tobe referred to as compound A hereinafter) (Ann. Chim. (Rome), 57 (6),688-97 (1967), Chem. Pharm. Bull., 18 (9), 1822-30 (1970) and Chem.Pharm. Bull., 19 (8), 1669-80 (1971)). However, there is no disclosureon its medicinal use.

Great concern is still directed toward the development of a vascularendothelial growth factor (VEGF) inhibitor useful as a therapeutic drugfor diseases in which angiogenesis is concerned such as cancers,particularly solid tumors, diabetic retinopathy and the like,particularly a drug which can be orally administered.

DISCLOSURE OF THE INVENTION

The present inventors have conducted extensive studies on a compoundwhich inhibits angiogenesis based on the VEGF inhibitory action andfound as a result that a 3-quinolin-2(1H)-ylideneindolin-2-onederivative in which the 2-position of the quinoline ring and the3-position of the indolinone ring are directly bonded and the doublebond is isomerized has good VEGF inhibitory action and is useful as anagent for the prevention or treatment of diseases which accompanyangiogenesis wherein VEGF is concerned, thereby resulting in theaccomplishment of the invention. As the compound in which the 2-positionof the quinoline ring and the 3-position of the indolinone ring aredirectly bonded and the double bond is isomerized, only theaforementioned compound A is known, and there are no reports on itsmedicinal use. The fact that a compound having said nucleus has a goodVEGF inhibitory action and is useful as a cancer treating drug is newinformation found by the present inventors.

That is, the present invention relates to a novel3-quinolin-2(1H)-ylideneindolin-2-one derivative represented by thefollowing general formula (I) or a salt thereof.

(Symbols in the formula have the following meanings;A, B, E, G and J: the same or different from one another and eachrepresents N atom or C atom,R¹ and R²: the same or different from each other and each represents alower alkyl, a lower alkenyl, a lower alkynyl, R^(a), X—(C₁₋₈ alkylenewhich may be substituted by OR^(b))—R^(a), X—(C₁₋₈ alkenylene)-R^(a) orX—(C₁₋₈ alkynylene)-R^(a), with the proviso that each of R¹ and R² doesnot substitute to the ring nitrogen atom,

X: O, CO, COO, OCO, S, SO, SO₂, NR^(b), NR^(b)SO₂, SO₂NR^(b), CONR^(b),NR^(b)CO, NR^(b)CONR^(c), NR^(b)COO, OCONR^(b) or a bond,

R^(a): a halogeno lower alkyl, a halogen, NO₂, CN, OR^(b), O-(loweralkylene)-NR^(b)R^(c), COOR^(b), COR^(b), CONR^(b)R^(c), NR^(b)R^(c),NR^(d)-(lower alkylene)-NR^(b)R^(c), NR^(d)-(lower alkylene)-OR^(b),N(lower alkylene-NR^(b)R^(c))₂, NR^(c)COR^(b), NR^(d)CONR^(b)R^(c),SR^(b), SO-lower alkyl, SO₂-lower alkyl, SO₂RIN, SO₂-(loweralkylene)-RIN, RIN, SO₂NR^(b)R^(c), NR^(c)SO₂R^(b), NR^(c)COOR^(b),OCO—NR^(b)R^(c), OCO—R^(b), NR^(d)-(lower alkylene)-COOR^(b), N(loweralkylene-COOR^(b))₂, CONR^(b)—OR^(c), CONR^(d)-(loweralkylene)-COOR^(b), CON(lower alkylene-COOR^(b))₂, CR^(d)═N—O—R^(c),CR^(d)═N—O-(lower alkylene)-COOR^(b) or CR^(d)═N—O-(loweralkylene)-NR^(b)R^(c),

R^(b), R^(c) and R^(d): the same or different from one another and eachrepresents H, a lower alkyl, a lower alkylene-RIN or RIN,

RIN: a saturated heterocyclic ring which may have one or moresubstituents, a cycloalkyl which may have one or more substituents, anaryl which may have one or more substituents or a heteroaryl which mayhave one or more substituents, and

n and m: the same or different from each other and each is 0 or aninteger of from 1 to 4, with the proviso that at least one of n and m isan integer of from 1 to 4 when all of A, B, E, G and J are carbon atom,the same shall apply hereinafter.)

It further relates to novel pharmaceutical compositions which comprise a3-quinolin-2(1H)-ylideneindolin-2-one derivative represented by thefollowing general formula (I′) or a salt thereof and a pharmaceuticallyacceptable carrier, particularly to a VEGF inhibitor, an angiogenesisinhibitor and an anti-tumor agent.

(Symbols in the formula have the following meanings;A, B, E, G and J: the same or different from one another and eachrepresents N atom or C atom,R¹ and R²: the same or different from each other and each represents alower alkyl, a lower alkenyl, a lower alkynyl, R^(a), X—(C₁₋₈ alkylenewhich may be substituted by OR^(b))—R^(a), X—(C₁₋₈ alkenylene)-R^(a) orX—(C₁₋₈ alkynylene)-R^(a), with the proviso that each of R¹ and R² doesnot substitute to the ring nitrogen atom,

X: O, CO, COO, OCO, S, SO, SO₂, NR^(b), NR^(b)SO₂, SO₂NR^(b), CONR^(b),NR^(b)CO, NR^(b)CONR^(c), NR^(b)COO, OCONR^(b) or a bond,

R^(a): a halogeno lower alkyl, a halogen, NO₂, CN, OR^(b), O-(loweralkylene)-NR^(b)R^(c), COOR^(b), COR^(b), CONR^(b)R^(c), NR^(b)R^(c),NR^(d)-(lower alkylene)-NR^(b)R^(c), NR^(d)-(lower alkylene)-OR^(b),N(lower alkylene-NR^(b)R^(c))₂, NR^(c)COR^(b), NR^(d)CONR^(b)R^(c),SR^(b), SO-lower alkyl, SO₂-lower alkyl, SO₂RIN, SO₂-(loweralkylene)-RIN, RIN, SO₂NR^(b)R^(c), NR^(c)SO₂R^(b), NR^(c)COOR^(b),OCO—NR^(b)R^(c), OCO—R^(b), NR^(d)-(lower alkylene)-COOR^(b), N(loweralkylene-COOR^(b))₂, CONR^(b)—OR^(c), CONR^(d)-(loweralkylene)-COOR^(b), CON(lower alkylene-COOR^(b))₂, CR^(d)═N—O—R^(c),CR^(d)═N—O-(lower alkylene)-COOR^(b) or CR^(d)═N—O-(loweralkylene)-NR^(b)R^(c),

R^(b), R^(c) and R^(d): the same or different from one another and eachrepresents H, a lower alkyl, a lower alkylene-RIN or RIN,

RIN: a saturated heterocyclic ring which may have one or moresubstituents, a cycloalkyl which may have one or more substituents, anaryl which may have one or more substituents or a heteroaryl which mayhave one or more substituents, and

n and m: the same or different from each other and each is 0 or aninteger of from 1 to 4, the same shall apply hereinafter.)

In this connection, the compound A known by the aforementionedreferences is included in the 3-quinolin-2(1H)-ylideneindolin-2-onederivative of the invention represented by the general formula (I′).

The compounds of general formulae (I) and (I′) are further described.

The term “lower” as used herein means a straight or branched hydrocarbonchain having from 1 to 6 carbon atoms. Accordingly, the “lower alkyl” ispreferably an alkyl group having from 1 to 4 carbon atoms, particularlypreferably a methyl, ethyl, propyl, isopropyl or isobutyl group. The“lower alkenyl” include preferably vinyl, allyl, 1-propenyl,isopropenyl, 1-butenyl, 2-butenyl and 3-butenyl groups. The “loweralkynyl” include preferably ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl and 1-methyl-2-propynyl groups. Also, preferred asthe “lower alkylene” include methylene, ethylene, trimethylene and2,2-dimethyltrimethylene groups. The “C₁₋₈ alkylene”, “C₁₋₈ alkenylene”and “C₁₋₈ alkynylene” mean straight or branched chain alkylene,alkenylene and alkynylene groups having from 1 to 8 carbon atoms.

Regarding the “cycloalkyl”, it is preferably a cycloalkyl group havingfrom 3 to 8 carbon atoms and particularly preferably includescyclopropyl, cyclopentyl and cyclohexyl. The “aryl” means an aromatichydrocarbon ring group, and an aryl group having from 6 to 14 carbonatoms is preferable and it may be partially saturated. Preferred arephenyl and naphthyl groups. The “heteroaryl” is a heteroaryl grouphaving a five- or six-membered monocyclic ring containing from 1 to 4hetero atoms selected from O, S and N, which may be condensed withbenzene ring and/or partially saturated. Its preferred examples includefuryl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furazanyl, thiazolyl,isothiazolyl, oxazolyl, isoxazole, oxadiazolyl, triazolyl, tetrazolyl,pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl,isoindolyl, benzimidazolyl, quinolyl, isquinolyl, dihydrooxazolyl,5,6-dihydro-4H-oxazinyl, imidazolinyl, pyrrolinyl, pyrazolinyl,indolinyl, isoindilinyl and the like.

As the “halogen”, F, Cl, Br and I atoms can be exemplified. The“halogeno lower alkyl” is the aforementioned lower alkyl groupsubstituted by at least one of the aforementioned halogen atoms, and ispreferably trifluoromethyl group.

The “saturated heterocyclic ring” is a 3- to 8-membered, preferably 5-to 7-membered, saturated heterocyclic ring group containing from 1 to 4of N, O or S atom as a ring atom, which may have a cross linking or mayform spiro-ring with another saturated heterocyclic ring or cycloalkyl(including 1,3-dioxolan and the like acetal compounds derived from oxogroups), and its preferred examples include aziridinyl, azetidinyl,pyrrolidinyl, piperazinyl, piperidyl, morpholinyl, thiomorpholinyl,pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, quinuclidinyl,oxiranyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, dioxolanyl,oxetanyl, perhydrothiazinyl, tetrahydrothienyl and tetrahydrofuranylgroups, of which particularly preferred are piperazinyl, piperidyl,morpholinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, dioxolanyl andoxetanyl groups.

In the aforementioned “heteroaryl” and “saturated heterocyclic ring”, anoptional C atom as a ring atom may be substituted by an oxo group, and aoxide or dioxide in which S or N atom is oxidized may be formed.

Regarding substituents of the “saturated heterocyclic ring which mayhave one or more substituents”, “cycloalkyl which may have one or moresubstituents”, “aryl which may have one or more substituents” and“heteroaryl which may have one or more substituents”, they arepreferably groups of the following G1 and G2 classes. More preferred aregroups of the G2 class, further preferred are groups of a G3 class, andparticularly preferred are groups of a G4 class. In this case, each ofR^(e), R^(f) and R^(g) represents H or a lower alkyl.

G1 class: a lower alkenyl, a lower alkynyl, a halogeno lower alkyl, NO₂,NR^(e)COR^(f), NR^(e)CONR^(f)R^(g), SR^(e), SO-lower alkyl, SO₂-loweralkyl and (aryl which may be substituted by one or more substituentsselected from the group consisting of a lower alkyl, a halogen, OR^(e),NR^(e)R^(f), COOR^(e), COR^(e), CONR^(e)R^(f) and an oxo group).

G2 class: (a lower alkyl which may be substituted by one or moresubstituents selected from the group consisting of OR^(e), NR^(e)R^(f),COOR^(e), COR^(e), CONR^(e)R^(f), a cycloalkyl, a heteroaryl and (asaturated heterocyclic ring which may be substituted by one or morelower alkyl groups)), a halogen, OR^(e), NR^(e)R^(f), COOR^(e), COR^(e),CONR^(e)R^(f), oxo, CN, (a saturated heterocyclic ring which may besubstituted by one or more substituents selected from the groupconsisting of a lower alkyl, a halogen, OR^(e), NR^(e)R^(f), COOR^(e),COR^(e), CONR^(e)R^(f) and an oxo group), a cycloalkyl and (a heteroarylwhich may be substituted by one or more substituents selected from thegroup consisting of a lower alkyl, a halogen, OR^(e), NR^(e)R^(f),COOR^(e), COR^(e), CONR^(e)R^(f) and an oxo group).

G3 group: {a lower alkyl which may be substituted by one or moresubstituents selected from the group consisting of OR^(e), NR^(e)R^(f),COOR^(e), COR^(e), CONR^(e)R^(f), a heteroaryl and (a saturatedheterocyclic ring which may be substituted by one or more lower alkylgroups)}, a halogen, OR^(e), NR^(e)R^(f), COOR^(e), COR^(e),CONR^(e)R^(f), (a saturated heterocyclic ring which may be substitutedby one or more lower alkyl groups), a cycloalkyl and a heteroaryl.

G4 class: a lower alkyl and a cycloalkyl.

According to the invention, two or more of the R¹ or R² are present whenm or n is an integer of from 2 to 4, and respective members of R¹ or R²may be the same or different from one another. The R¹ may be substitutedon any one of the 3- to 8-positions of the quinoline ring. A compound inwhich R¹ is substituted on the 5- or 6-position of the quinoline ring,and a compound in which R² is substituted on the 5- or 6-position of theindolinone ring are more preferable.

Among the compounds (I) and (I′) of the invention, the following can becited as preferred compounds.

(1) A compound in which A, B and E are (a) A and B are N atom and E is Catom, (b) one of A and E is N atom and the other is C atom, and B is Catom or (c) A, B and E are C atom; and G and J are both C atom or one ofthem is N atom and the other is C atom,

(2) a compound in which A, B, E, G and J are all C atom,

(3) a compound in which R¹ and R² may be the same or different from eachother and each represents a lower alkyl, a lower alkenyl, a loweralkynyl, R^(a), X—(C₁₋₈ alkylene which may be substituted by OH)—R^(a),X—(C₁₋₈ alkenylene)-R^(a) or X—(C₁₋₈ alkynylene)-R^(a); R^(a) is ahalogeno lower alkyl, a halogen, NO₂, CN, OR^(b), O-(loweralkylene)-NR^(b)R^(c), COOR^(b), COR^(b), CONR^(b)R^(c), NR^(b)R^(c),NR^(d)-(lower alkylene)-NR^(b)R^(c), NR^(d)-(lower alkylene)-OR^(b),N(lower alkylene-NR^(b)R^(c))₂, NR^(c)COR^(b), NR^(d)CONR^(b)R^(c),SR^(b), SO-lower alkyl, SO₂-lower alkyl, RIN, SO₂NR^(b)R^(c),NR^(c)SO₂R^(b), NR^(c)COOR^(b) or OCO—NR^(b)R^(c); and R^(b), R^(c) andR^(d) may be the same or different from one another and each representsH, a lower alkyl or RIN,

(4) a compound in which X is O, CO, COO, S, NR^(b), CONR^(b), NR^(b)CO,NR^(b)SO₂, NR^(b)CON^(c) or a bond,

(5) a compound in which m is 0, 1 or 2; R² is a lower alkyl, R^(a2) orX²—(C₁₋₈ alkylene)-R^(a2); X² is O, CO, COO, NR^(b), CONR^(b) or a bond;and R^(a2) is a halogeno lower alkyl, a halogen, NO₂, CN, OR^(b),COOR^(b), COR^(b), CONR^(b)R^(c), NR^(b)R^(c), NR^(c)COR^(b), SO₂-loweralkyl, RIN, SO₂NR^(b)R^(c), OCO—R^(b), CONR^(b)—OR^(c), CR^(d)═N—OR^(c)or CR^(d)═N—O-(lower alkylene)-NR^(b)R^(c),

(6) a compound in which n is 0, 1 or 2; R¹ is a lower alkyl, R^(a1) orX¹—(C₁₋₈ alkylene which may be substituted with OR^(b))—R^(a1); X¹ is O,CONR^(b), NR^(b)CO, NR^(b)CONR^(c) or a bond; and R^(a1) is a halogen,NO₂, CN, OR^(b), COOR^(b), COR^(b), CONR^(b)R^(c), NR^(b)R^(c),NR^(d)-(lower alkylene)-NR^(b)R^(c), NR^(d)-(lower alkylene)-OR^(b),NR^(d)CONR^(b)R^(c), RIN, OCO—R^(b), NR^(d)-(lower alkylene)-COOR^(b) orCONR^(b)—OR^(c), and

(7) a compound in which n is 1 or 2 and R¹ is a halogen, a lower alkyl,CN, O—C₁₋₈ alkylene-(saturated heterocyclic ring which may besubstituted by one or more substitutents selected from G2 class), C₁₋₈alkylene-(saturated heterocyclic ring which may be substituted by one ormore substitutents selected from G2 class), C₁₋₈ alkylene-NR^(e)-(loweralkylene)-(saturated heterocyclic ring which may be substituted by oneor more substitutents selected from G2 class), CO-(saturatedheterocyclic ring which may be substituted by one or more substitutentsselected from G2 class), C₁₋₈ alkylene-(a substitutent selected from thegroup consisting of COOR^(e), NR^(e)R^(f), cycloalkyl and heteroaryl),or O—C₁₋₈ alkylene-(a substitutent selected from the group consisting ofCOOR^(e), NR^(e)R^(f), cycloalkyl and heteroaryl); and m is 0, 1 or 2and R² is a halogen, a lower alkyl, CO₂R^(e) or CR^(e)═N—OR^(f),

(8) a compound in which n is 1 and R¹ is —C₁₋₈ alkylene-(saturatedheterocyclic ring which may be substituted by one or more substitutentsselected from G4 class), C₁₋₈ alkylene-(saturated heterocyclic ringwhich may be substituted by one or more substitutents selected from G4class), C₁₋₈ alkylene-NR^(e)-(saturated heterocyclic ring which may besubstituted by one or more substitutents selected from G4 class), C₁₋₈alkylene-NR^(e)-(lower alkylene)-(saturated heterocyclic ring which maybe substituted by one or more substitutents selected from G4 class),CO-(saturated heterocyclic ring which may be substituted by one or moresubstitutents selected from G4 class), C₁₋₈ alkylene-COOR^(e), C₁₋₈alkylene-NR^(e)R^(f), or O—C₁₋₈ alkylene-COOR^(e) and O—C₁₋₈alkylene-NR^(e)R^(f),

(9) a compound in which m is 1, R² is CR^(g)═N—O-(loweralkylene)-(heteroaryl which may be substituted by one or moresubstitutents selected from G2 class), and n is 0,

(10) a compound in which R² is CR^(g)═N—O-(lower alkylene)-(heteroarylwhich may be substituted by one or more substitutents selected from G4class), and

(11) compounds listed below and salts thereof,3-[6-(2-morpholin-4-ylethoxy)quinolin-2(1H)-ylidene]indolin-2-one,3-(6-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}quinolin-2(1H)-ylidene)indolin-2-one,3-{6-[(tetrahydro-2H-pyran-4-ylamino)methyl]quinolin-2(1H)-ylidene}indolin-2-one,3-{6-[(4-methylpiperazin-1-yl)methyl]quinolin-2(1H)-ylidene}indolin-2-one,3-{6-[(4-ethylpiperazin-1-yl)methyl]quinolin-2(1H)-ylidene}indolin-2-one,3-{6-[(4-cyclohexylpiperazin-1-yl)methyl]quinolin-2(1H)-ylidene}indolin-2-one,and3-[6-(4-methylpiperazine-1-carbonyl)quinolin-2(1H)-ylidene]indolin-2-one.

The compounds (I) and (I′) of the invention have theoretically possibletwo or more tautomers or stereoisomers in the conjugate systemstretching from the 1-position nitrogen atom of the quinoline ring tothe 1-position nitrogen atom of the indolinone ring, and separated formsor mixtures of these isomers are included in the invention.

Depending on the kinds of substituents, geometrical isomers andtautomers may be further present in the compounds of the invention, andseparated forms or mixtures of these isomers are included in theinvention. In addition, since the compounds of the invention haveasymmetric carbon atoms in some cases, isomers based on these asymmetriccarbon atoms can exist. Mixtures and separated forms of these opticalisomers are included in the invention.

Also, the compounds of the invention form salts in some cases. Thoughnot particularly limited so far as they are pharmaceutically acceptablesalts, illustrative examples of the acid addition salt include acidaddition salts with inorganic acids (e.g., hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,phosphoric acid and the like) and organic acids (e.g., formic acid,acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid,glutamic acid and the like), and examples of the salt with base includesalts with inorganic bases containing metals (e.g., sodium, potassium,magnesium, calcium, aluminum and the like) or with organic bases (e.g.,methylamine, ethylamine, ethanolamine, lysine, ornithine and the like),and ammonium salts. Still more, the invention also includes varioushydrates, solvates and polymorphic substances of the compound (I) of theinvention and salts thereof.

In addition, pharmacologically acceptable prodrugs are also included inthe compounds of the invention. The pharmacologically acceptable prodrugis a compound having a group which is converted into NH₂, NH, OH, CO₂Hor the like of the invention by solvolysis or under a physiologicalcondition. Examples of the group for forming a prodrug include thosewhich are described in Prog. Med., 5, 2157-2161 (1985) and “Iyakuhin noKaihatsu (Development of Medicaments)” (Hirokawa Shoten, 1990) vol. 7,Bunshi Sekkei (Molecular Designing) 163-198. For example, OCO-(loweralkylene which may have one or more substituents)-COOR (R represents Hor a lower alkyl, the same shall apply hereinafter), OCO-(loweralkenylene which may have one or more substituents)-COOR, OCO-(arylwhich may have one or more substituents), OCO-(lower alkylene)-O-(loweralkylene)-COOR, OCO—COR, OCO-(a lower alkyl which may have one or moresubstituents), OSO₂-(a lower alkylene which may have one or moresubstituents)-COOR, O-phthalidyl,5-methyl-1,3-dioxolen-2-on-4-yl-methyloxy or the like is suitable as thegroup which is converted into OH; OCHR—O—CO-lower alkyl,OCHRO—CO—O-lower alkyl, 5-methyl-1,3-dioxolen-2-on-4-yl-methyloxy or thelike is suitable as the group which is converted into CO₂H; andNHCO—OCH₂—OCO-lower alkyl, NCONH-lower alkyl, 2-tetrahydrofurfurylamino,1-pyrrolidylmethylamino, an NCH₂OCO-lower alkyl,5-methyl-1,3-dioxolen-2-on-4-yl-methyloxycarbonylamino or the like issuitable as the group which is converted into NH₂ or NH.

(Production Methods)

The compound of the invention can be easily produced by those methodswhich are similar to the methods described in references, e.g., Chem.Pharm. Bull., 18 (9), 1822-30 (1970), J. Am. Chem. Soc., 122 (7),1360-70 (2000) and the like, or methods known to those skilled in theart.

In this connection, depending on the kinds of functional groups, it iseffective in some cases from the viewpoint of production techniques toreplace said functional groups with appropriate protecting groups,namely those groups which can be converted into said functional groups,at the stage of the starting materials or intermediates. Thereafter, thedesired compound can be obtained by removing the protecting groups asoccasion demands. Examples of such functional groups include thosegroups which are described in “Protective Groups in Organic Synthesis”3rd edition, edited by Greene and Wuts, and these may be optionally usedin response to the reaction conditions.

Typical production methods are described in the following.

(In the formula, R³ represents a protecting group such asdiethoxymethyl, p-toluenesulfonyl, trimethylsilylethylsulfonyl or thelike, and L represents a leaving group applicable to said reaction, suchas a halogen, sulfonate or the like. The same shall apply hereinafter.)First Production Method

The compound (I) of the invention can be produced by allowing aquinoline N-oxide compound (II) to react with an indolinone (V) in theusual way. The reaction can be carried out by optionally applying themethod described, for example, in Ann. Chim. (Rome), 57 (6), 188-97(1967), Khim. Geterotsikl. Soedin., 10, 1371-3 (1970), Chem. Pharm.Bull., 18 (9), 1822-30 (1970) and Chem. Pharm. Bull., 19 (8), 1669-80(1971), and it is advantageous to carry out the reaction in a solventinert to the reaction (e.g., chloroform, acetonitrile or the like) atordinary temperature or under heating, preferably at reflux temperatureof the solvent, using reaction-corresponding amounts of the compounds(II) and (V) or one of them in excess amount, and using an appropriateacylation agent (benzoyl chloride, acetic anhydride or the like),sulfonylation agent (p-toluenesulfonyl chloride or the like), alkylationagent (methane iodide or the like) or silylation agent(chlorotrimethylsilane or the like) as the activation agent. When aceticanhydride is used, it is advantageous to use it as the solvent, it isdesirable to carry out the reaction at ordinary temperature or underheating.

Second Production Method

In the first step, the compound (III) can be produced in accordance withthe method described in J. Am. Chem. Soc., 122 (7), 1360-70 (2000) orthe like, by carrying out the reaction in a solvent inert to thereaction (e.g., toluene, tetrahydrofuran (THF) or the like) at ordinarytemperature or under heating using reaction-corresponding amounts of thecompounds (IV) and (VI) or one of them in excess amount, in the presenceof a base (e.g., sodium tert-butoxide or the like), and by treating witha palladium complex (e.g., palladium acetate, palladium chloride,dibenzylideneacetone dipalladium or the like). The reaction willprogress advantageously in some cases when a ligand of the palladiumcomplex (e.g., BINAP, DPPF, Xantphos or the like) is added as occasiondemands.

Next, the compound (I) of the invention can be produced in the secondstep, by deprotecting the compound (III) in the presence of an acid(e.g., hydrochloric acid or the like) in accordance with the methoddescribed in WO 97/42187 or the like, or in the presence of a reducingagent (e.g., tributyltin hydride or the like) in accordance with themethod described in Tetrahedron, 56 (7), 979-988 (2000) or the like.Third Production Method

(In the formula, hal represents a halogen, and R⁴ represents a loweralkyl. The same shall apply hereinafter.)

The first step can be easily carried out in accordance with knownreaction conditions (e.g., J. Med. Chem., 42, 5120-5130 (1999) or thelike). The compound (X) can be produced by carrying out the reaction ina solvent inert to the reaction (e.g., N,N-dimethylformamide (DMF),dimethyl sulfoxide (DMSO), THF or the like) at ordinary temperature orunder heating using reaction-corresponding amounts of the compounds(VIII) and (IX) or one of them in excess amount, in the presence of abase (e.g., sodium hydride, sodium tert-butoxide or the like) or an acid(e.g., acetic acid). Next, the compound (I) of the invention can beproduced in the second step, by reducing nitro group of the compound (X)in accordance with a conventional reducing reaction such as the methoddescribed in J. Med. Chem., 42, 5120-5130 (1999) or the like. Thereaction will progress advantageously in some cases when heated orpressurized as occasion demands. It is possible to carry out conversionof a substituent in the compound (X) during this process by employingconditions of a conventional method. For example, when R² is a leavinggroup typified by a halogen or the like, it can be replaced by an aminederivative by an ipso substitution reaction, and when R¹ and R² arealdehyde, ketone and the like, they can be converted into oximecompounds and the like by condensation reaction and the like.

Other Production Methods

The compound of the invention can be produced by various knownsubstituent modification reactions, in addition to the aforementionedproduction methods. For example, it can be easily produced withreference to the conditions described in references or cited referencestherein such as COMPREHENSIVE ORGANIC SYNTHESIS, edited by B. M. Trost(Pergamon Press) (1991), COMPREHENSIVE ORGANIC TRANSFORMATIONS, editedby R. C. Larock (VCH Publishers) (1989), ADVANCED ORGANIC CHEMISTRY,edited by J. March (John WILEY & SON) (1992), “Jikken Kagaku Koza(Experimental Chemistry Course)” 4th edition, edited by The ChemicalSociety of Japan (Maruzen) or the like. Main production methods aredescribed in the following.

A compound having an aminoalkyl group-containing substituent can beeasily produced (1) from a compound having a halogen-substituted alkylgroup or an epoxide by a conventional amination reaction, (2) from acompound having an aldehyde or ketone by a conventional reductiveamination reaction (e.g., Tetrahedron Lett., 31, 5595-5598 (1990) or thelike can be used as a reference) or (3) from a compound having aprotected aminoalkyl group by a deprotection reaction (e.g., treatmentwith hydrochloric acid, trifluoroacetate (TFA) or the like in the caseof tert-butoxycarbonyl group (Boc) or treatment with hydrazine ormethylamine in the case of phthalimido group).

In case that reaction of the reductive amination reaction hardlyprogresses by the use of a ketone or a secondary amine or a combinationof a ketone and a secondary amine, it is desirable to produce thecompound by a method similar to the method described, for example, in J.Org. Chem., 55 (8), 2552 (1990).

A compound having an ether bond-containing substituent can be producedfrom a compound having phenol or hydroxyl group by conventionalO-alkylation reaction or the Mitsunobu reaction described, for example,in Tetrahedron Lett., 40 (4), 671-674 (1999), Chem. Lett., (2), 97-98(1996) or Helv. Chim. Acta, 81 (5), 865-880 (1998). A compound having anamino group-containing substituent can be produced from a compoundhaving nitro group via a conventional reduction reaction.

A compound having hydroxyl group can be produced (1) from a compoundhaving an ester group or the like by a conventional hydrolysis reactionor (2) from a compound having benzyl group or the like by a conventionalhydrogenolysis reaction. A compound having carboxyl group can beproduced from a compound having an ester group by a conventionalhydrolysis reaction, particularly by a hydrogenolysis in the case of anester comprising benzyl alcohol or the like. A compound having amidobond can be produced by a conventional amidation reaction which uses anamino group-containing compound of the invention and an acid chloride, amixed acid anhydride, carbodiimide or the like, or a conventionalamidation reaction which uses a carboxyl group-containing compound ofthe invention and an amine.

A compound having a hydroxamic acid ester can be produced from acarboxyl group-containing compound of the invention by a conventionalamidation reaction which uses hydroxylamines. A compound having anO-substituted oxime-containing substituent can be produced from analdehyde- or ketone-containing compound of the invention by aconventional dehydration condensation reaction or the like which usesO-substituted hydroxylamines. A compound having urea bond-containingsubstituent can be produced from a compound having amino group by aconventional urea introducing reaction or the like which uses anisocyanate or mediates a phenylcarbamate derivative.

An N-oxide compound can be produced by a known oxidation reaction,namely by the reaction with an oxidation agent (e.g., m-chloroperbenzoicacid, hydrogen peroxide or the like) in a reaction-inert solvent (e.g.,chloroform, dichloromethane or the like). It is possible to convert asulfide into a sulfoxide or a sulfone under the same oxidationcondition. When it is planned to obtain a desired compound from aprecursor compound having an N-hydroxyamido bond by carrying out ade-hydroxylation reaction, it can be easily carried out by mediating aconventional reducing condition (e.g., a reaction with metallic iron inacetic acid, a hydrogenolysis reaction or the like). Introduction of anaromatic hetero ring can be easily carried out by a method in which asubstituent having a precursor is introduced and then converted into ahetero ring by a conventional condensation reaction.

(Synthesis of Starting Compounds)

Some of the starting compounds of the compound of the invention arenovel compounds, and these compounds can be easily synthesized in thesame manner as the known starting compounds or using certain methodsknown to those skilled in the art. Typical synthesis methods are shownbelow. Synthesis method 1 (alkylation) References: J. Med. Chem., 40,1252-1257 (1997) and the like

(In the formula, p is an integer of 1 to 8. The same shall applyhereinafter.)Synthesis Method 2 (Oxidation) References: Synthesis, 87-90 (1997) andthe Like

Synthesis Method 3 References: J. Heterocyclic Chem., 15, 1425-1430(1978) and the Like

The quinolineacetic acid derivative (IX) can be produced in the usualway by treating the compound (II) with ethyl acetoacetate, dietylmalonate or the like in the presence of an appropriate acylation agent,sulfonylation agent, alkylation agent or silylation agent.Synthesis Method 4 (Sonogashira Reaction) References: Synthesis, 364-365(1981) and the Like

(In the formula, R³ represents a substituted alkyl or O-substitutedalkyl.)Synthesis Method 5 (Halogenation) References: J. Am. Chem. Soc., 77,1054-1055 (1955), Tetrahedron, 54, 13655-13680 (1998) and the Like

Synthesis Methods for other Starting Compounds

A compound having a substituent group on the quinoline ring can also beproduced, for example, by employing the methods described inHeterocycles, 54, 105-108 (2001) and J. Med. Chem., 26, 580-585 (1983),or a method in which a 4-chloroquinoline derivative is produced byapplying Org. Synth. Col., Vol. 3, 272 (1955), Syn. Commun., 15, 125(1995) or the like and then the chloro group is removed by aconventional method via a reducing condition and the like.

Regarding synthesis of the indolinone ring, it can be easily produced byemploying the conditions described in Synthesis, 51-53 (1993), Eur. J.Med. Chem., 15, 330-332 (1980) or the like.

Introduction of a substituent group onto the indolinone ring can becarried out by applying the Suzuki-Miyaura reaction of its halogenderivative or the Friedel-Crafts reaction, and a conversion reaction orthe like into the aromatic hetero ring via a condensation reaction whichuses the introduced α-halo ketone group. For example, it is possible toemploy the methods described in J. Med. Chem., 42, 5120-5130 (1999),Synthesis, 873-874 (1989), J. Org. Chem., 17, 1252-1255 (1952) and thelike. Also, it is possible to remove the introduced primary amine on thearomatic hetero ring, for example by applying the method described in J.Med. Chem., 39, 834-841 (1996).

In addition, as occasion demands, the starting compounds of interest canbe produced by subjecting to amination, imination, acylation,alkylation, amidation, sulfonamidation, esterification, urea introducingreaction, halogenation, nitration, oxidation, reduction, protection,deprotection and the like various known substituent group modificationreactions. These reactions can be carried out with reference to theconditions described in the aforementioned references such as “JikkenKagaku Koza” 4th edition, edited by The Chemical Society of Japan(Maruzen) or the like.

Isolation and purification of the compound of the invention produced inthis manner are carried out by employing extraction, concentration,crystallization, filtration, recrystallization, various chromatographytechniques and the like general chemical operations.

Each of the isomers can be isolated in the usual way by making use of adifference in the physicochemical property between isomers. For example,a racemic compound can be separated to optically pure isomer by ageneral optical resolution method [e.g., a method in which the compoundis introduced into diastereomer salts with a general optically activeacid (tartaric acid or the like) and then subjected to opticalresolution]. Also, a mixture of diastereomers can be separated forexample by fractional crystallization, a chromatography and the like. Inaddition, an optically active compound can also be produced by the useof an appropriate optically active material.

INDUSTRIAL APPLICABILITY

Since the drug of the invention has a VEGF inhibitory action, it isuseful in the treatment and improvement of diseases and morbid states inwhich VEGF is taking a role. Particularly, as an inhibitor ofangiogenesis caused by VEGF, it is useful for the growth inhibition ofcancers, particularly solid tumors, hemangioma and the like tumors, forthe prevention and treatment of rheumatoid arthritis, psoriasis,scleroderma and the like diseases, and for the prevention and treatmentof diabetic retinopathy and the like retinal diseases and neovascularglaucoma and the like eye diseases.

As is shown in the following test examples, the compound of theinvention showed good inhibitory activity upon the VEGF-stimulatedgrowth of vascular endothelial cells. Also, the compound of theinvention inhibited VEGF-dependent in vitro angiogenesis. Accordingly,it was revealed that the compound of the invention inhibits growth andangiogenesis of vascular endothelial cells caused by VEGF.

Since it has been confirmed that the compound of the invention inhibitscancer growth having a significance against control when it is orallyadministered in an anti-tumor test using COLO 205 (human colontumor)-bearing nude mice, it was suggested that it inhibits growth ofcancer via its action to inhibit VEGF-induced angiogenesis. Accordingly,it is useful as an angiogenesis inhibitor and an anti-tumor agent, whichcan be orally administered.

In addition, since the compound of the invention inhibits accelerationof vascular permeability caused by VEGF, it is also useful as an agentfor improving malignant ascites and pleural effusion production.

TEST EXAMPLE 1 Test on the Inhibition of VEGF-Stimulated HUVEC Growth

Test method: (Cell culture) Human umbilical vein endothelial cells(HUVEC) were cultured using EGM-2 complete medium (Clonetics) which hadbeen supplemented with additives (2% FBS, 0.4% FGF (fibroblast growthfactor), 0.1% VEGF, 0.1% IGF-I (insulin like growth factor-I), 0.1% EGF(epidermal growth factor), 0.1% ascorbic acid, 0.1% GA-1000, 0.1%heparin and 0.04% hydrocortisone).

(Evaluation of compounds) HUVEC (10,000 cells/well) were inoculated intoEGM-2 complete medium in a gelatin-coated 96 well plate (mfd. by IWAKI)and cultured overnight. After washing with a physiological phosphatebuffer, the medium was exchanged with a low serum medium (Medium199/0.1% FBS) and the culturing was continued for 24 hours. Each of thecompounds to be evaluated was prepared as a 10 mM DMSO solution anddiluted with the low serum medium. This was added to each well to afinal concentration of from 0.001 to 10 μM. After 2 hours of thecompound treatment, human recombinant VEGF (R & D Systems) was added toa final concentration of 10 ng/ml. After 18 hours, [³H]thymidine(Amersham Pharmacia) was added in 5 μCi/well portions. After 4 hours,the reaction was terminated by adding 0.2% SDS in 50 μl/well portions,and the product was recovered on GF/C Unifilter (Packard). After adding25 μl of Microscinti 20 (Packard), the radioactivity incorporated intothe DNA trapped on the filter was measured using TopCount (Packard). TheIC₅₀ of the inhibitory activity of each compound was calculated as the50% inhibition concentration (IC₅₀ value) of each compound to be tested,by defining the incorporated amount of [³H]thymidine at the time of VEGFaddition as 100%, and its incorporated amount at the time of no additionof VEGF as 0%.

Results: The results are shown in the following table. It was confirmedby this test that the compounds of the invention have good VEGFinhibitory action. TABLE 1 Ex. IC₅₀ No. (μM) Compound A 0.14  1 0.21  40.19  8 0.17  9 0.20  10 0.99  14 0.30  15 0.32  16 0.11  17 0.012  210.22  25 0.38  32 0.013  36 0.16  37 0.31  38 0.038  39 0.032  40 0.0062 41 0.12  42 0.11  44 0.28  45 0.036  46 0.12  47 0.17  48 0.54  53 0.16 54 0.029  56 0.11  57 0.72  58 0.034  59 0.087  66 0.35  77 0.16  790.10  80 0.10  81 0.068  82 0.042  83 0.11  85 0.11  86 0.10  87 0.10 96 0.15  98 0.15  99 0.13 102 0.41 105 0.22 111 0.30 112 0.10 144 0.093145 0.031 146 0.076 148 0.074 149 0.073 159 0.038 160 0.046 161 0.10 1630.043 175 0.098 177 0.11 187 0.14 191 0.070 193 0.87 201 0.29 203 0.0048204 0.022 209 0.018 213 0.00097 217 0.011 222 0.0068 239 0.31 242 0.045259 0.071 265 0.18 283 0.084 284 0.36 285 0.070 286 0.75 288 0.038 2930.048 294 0.012 295 0.033 296 0.047 297 0.031 298 0.050 299 0.027 3010.0076 310 0.31 311 0.24 312 0.048 341 0.020 354 0.14 361 0.024

TEST EXAMPLE 2 In Vitro Angiogenesis Inhibition Test

Test method: An angiogenesis assay kit (mfd. by KURABO was used. Amedium prepared by adding 10 ng/ml of VGEF (R & D Systems) to thespecial medium attached to the kit used as the culture medium. Each testdrug was prepared as a 10 mM DMSO solution and added to a finalconcentration of from 0.003 to 1 μM by diluting with the special medium.Amount of angiogenesis under a condition of not adding the test drug wasused as the positive control, and a condition under which 25 μg/ml of ananti-VEGF antibody (Sigma) was added was used as the negative control.On the 4th, 7th and 10th days after commencement of the culturing, thetest drug was prepared as described in the above and exchanged with themedium of each well. On the 13th day, fixation of the cell layer wascarried out in accordance with the method attached to the kit. That is,fixation of cell layer was carried out by adding ice-cooled 70% ethanolafter washing with a physiological phosphate buffer and then allowing tostand at room temperature for 30 minutes. Next, the ethanol solution wasremoved by sucking, followed by washing with a blocking solution(physiological phosphate buffer containing 1% BSA).

A endotherial vessel staining kit CD31 for staining (mfd. by KURABO) wasused for the staining of the thus formed hollow organ. That is, themouse anti-human CD31 antibody attached to the kit was diluted 4,000times with the blocking solution and added to each well to carry out theincubation at 37° C. for 60 minutes. Subsequently, after washing threetimes with the blocking solution, a goat anti-mouse IgG alkalinephosphatase conjugate solution diluted 500 times with the blockingsolution was added to each well and incubated at 37° C. for 60 minutes.After the incubation, each well was washed three times with distilledwater. Next, a BCIP/NBT solution prepared by dissolving in distilledwater was added to each well and incubated at room temperature for 5 to10 minutes. After the incubation, this was washed three times withdistilled water and then spontaneously dried. Under a microscope, thestained endotherial vessel image was photographed at 4 positions aroundthe center of each well and preserved by a TIFF mode. An imagingsoftware (ScnImage) shown in the angiogenesis kit was used for thedetermination of the endotherial vessel forming amount. By importing thefile preserved in the imaging software, the number of pixel obtained bythreshold and measure commands was recorded. Average of the number ofpixel at the 4 positions obtained from 1 well was used as theendotherial vessel forming amount in said well.

The IC₅₀ value of each test drug was calculated as the 50% inhibitingconcentration of the test drug, by defining the number of pixel in apositive control well under a test drug-non-added condition as 100%, andthe number of pixel in a negative control well under an anti-VEGFantibody-added condition as 0%.

Results: The compounds of the invention showed excellent activity inthis test; for example, IC₅₀ value of the compound A was 0.069 μM.

TEST EXAMPLE 3 In Vivo Anti-Tumor Test Using Human Colon Tumor BearingNude Mice

Test method: A total of 4×10⁶ cells of a human colon tumor COLO 205 wereadministered under the dorsal side skin of each female Balb/c nudemouse. When the tumor volume reached 50 to 100 mm³, each of the testcompounds was orally administered once a day for 14 days. In addition,0.5% methyl cellulose aqueous solution was orally administered to thecontrol group. Calipers were used for the measurement of tumor diameter,and it was measured on the next day of the final administration. In thiscase, the tumor volume was calculated using the following calculationformula.Tumor volume=(width²×length)/2

Results: It was confirmed by this test that the compounds of Examples 4,41, 44, 54, 96, 99, 111, 113, 115, 132, 134, 148, 310 and 311 of theinvention inhibit the tumor growth with a significance for the control,by their oral administration at a dose of 10 or 30 mg/kg/day.

The pharmaceutical composition which contains one or two or more of thecompounds represented by the general formula (I) or salts thereof as theactive ingredient is prepared by a generally used method usingpharmaceutical carriers, fillers and the like generally used in thisfield. It may be administered either by oral administration in the formof tablets, pills, capsules, granules, powders, solutions inhalationsand the like, or by parenteral administration in the form ofintravenous, intramuscular and the like injections, suppositories,ophthalmic solutions, ophthalmic ointments, solutions for percutaneousabsorption, ointments, adhesives for percutaneous absorption,transmucosal solutions, transmucosal adhesive preparations and the like.

The solid composition for use in the oral administration according tothe present invention is used in the form of tablets, powders, granulesand the like. In such a solid composition, one or more active substancesare mixed with at least one inert diluent such as lactose, mannitol,glucose, hydroxypropylcellulose, microcrystalline cellulose, starch,polyvinyl pyrrolidone, aluminum magnesium silicate or the like. Inaccordance with the usual way, the composition may contain otheradditives than the inert diluent, such as a lubricant (e.g., magnesiumstearate or the like), a disintegrating agent (e.g., calcium celluloseglycolate or the like), a stabilizing agent and a solubilizationassisting agent. If necessary, tablets or pills may be coated with asugar coat or a film of a gastric or enteric substance such as sucrose,gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalateor the like.

The liquid composition for oral administration includes pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, elixirs and thelike and contains a generally used inert diluent such as purified wateror ethanol. In addition to the inert diluent, this composition may alsocontain a moistening agent, a suspending agent and the like auxiliaryagents, as well as sweeteners, flavors, aromatics and antiseptics.

The injections for parenteral administration includes aseptic aqueous ornon-aqueous solutions, suspensions and emulsions. Examples of thediluent for use in the aqueous solutions and suspensions includedistilled water for injection and physiological saline. Examples of thediluent for use in the non-aqueous solutions and suspensions includepropylene glycol, polyethylene glycol, a plant oil (olive oil or thelike), an alcohol (ethanol or the like), polysorbate 80 (trade name) andthe like. Such a composition may further contain auxiliary agents suchas an antiseptic, a moistening agent, an emulsifying agent, a dispersingagent, a stabilizing agent and a solubilization assisting agent. Thesecompositions are sterilized by filtration through a bacteria retainingfilter, blending of a germicide or irradiation. Alternatively, these maybe used by producing sterile solid compositions and dissolving them insterile water or a sterile solvent for injection prior to their use.

In general, a daily dose of approximately from 0.001 to 50 mg/kg,preferably from 0.01 to 10 mg/kg, per body weight in the case of oraladministration, and a daily dose of approximately from 0.0001 to 5 mg/kgper body weight in the case of intravenous administration, arerespectively suitable, and the daily dose is divided into 1 to severaldoses per day. The dose is optionally decided in response to each caseby taking symptoms, age, sex and the like into consideration.

BEST MODE FOR CARRYING OUT THE INVENTION

The following describes the invention further in detail based onexamples. Production methods of starting compounds to be used inExamples are shown in reference examples. In this connection, thecompounds of the invention are not limited to the compounds described inthe following Examples.

Also, abbreviations of physicochemical properties described in thereference examples, Examples and subsequent tables indicate,

F+: FAB-MS (M+H)⁺; F−: FAB-MS (M−H)⁻; F: FAB-MS (M)⁺; E+: ESI-MS (M+H)⁺;E: ESI-MS (M)⁺; N1: characteristic peak δ ppm of ¹H-NMR (DMSO-d₆, TMSinternal standard); and N2: characteristic peak δ ppm of ¹H-NMR (CDCl₃,TMS internal standard).

REFERENCE EXAMPLE A1

A DMF solution of ethyl quinolin-2-ylacetate was mixed with 60% NaH andstirred, and then N,N-diethyl-4-fluoro-3-nitrobenzamide was addedthereto and stirred. By purifying the thus formed substance from thereaction solution, ethyl{4-[(diethylamino)carbonyl]-2-nitrophenyl}(quinolin-2(1H)-ylidene)acetatewas obtained as a brown foam. F+: 435.

REFERENCE EXAMPLE A2

2,4-Dichloro-5-nitropyrimidine was added to an acetic acid solution ofethyl quinolin-2-ylacetate and stirred at 50° C. After spontaneouscooling, the thus formed precipitate was collected by filtration toobtain ethyl(2-chloro-5-nitropyrimidin-4-yl)(quinolin-2(1H)-ylidene)acetate as a redsolid. F+: 373.

REFERENCE EXAMPLE A3

Morpholine was added to a pyridine solution of ethyl(5-fluoro-2-nitrophenyl)(quinolin-2(1H)-ylidene)acetate and stirred at100° C. and then the mixture was purified to obtain ethyl(5-morpholin-4-yl-2-nitrophenyl)(quinolin-2(1H)-ylidene)acetate as a redsolid. F+: 422.

REFERENCE EXAMPLE B1

Under ice-cooling, oxalyl chloride and a catalytic amount of DMF wereadded to a dichloromethane solution of 4-fluoro-3-nitrobenzoic acid andstirred. After evaporation of the solvent, the resulting residue wasdissolved in THF and, under ice-cooling, added dropwise to a THFsolution of O-(cyclopropylmethyl)hydroxylamine hydrochloride andtriethylamine (TEA). After stirring the reaction solution, the thusformed substance was purified to obtainN-(cyclopropylmethoxy)-4-fluoro-3-nitrobenzamide as a yellow solid. F+:255.

REFERENCE EXAMPLE B2

Ethyl chloroformate and TEA were added to a THF solution of2-oxoindoline-5-carboxylic acid and stirred. The reaction solution wasmixed with N,N-diethylethylenediamine, stirred and then purified toobtain N-[(2-diethylamino)ethyl]-2-oxoindoline-5-carboxamide as a brownsolid. F+: 276.

REFERENCE EXAMPLE C

An acetonitrile solution of 6-(2-bromoethoxy)quinoline N-oxide was mixedwith morpholine, stirred at 100° C. and then purified to obtain6-[(2-morpholin-4-yl)ethoxy]quinoline N-oxide as a light brown solid.F+: 275.

REFERENCE EXAMPLE D

Methoxylamine hydrochloride was added to a THF solution of4-bromo-2-methyl-5-nitrobenzaldehyde and stirred at 50° C. for 8 hours.By purifying the thus formed substance from the reaction solution,4-bromo-2-methyl-5-nitrobenzaldehyde O-methyloxime was obtained as acolorless oil. F−: 272, 274.

REFERENCE EXAMPLE E1

A DMF solution of 6-hydroxyquinoline was mixed with 60% NaH, and stirredat 50° C. After spontaneous cooling, the reaction solution was mixedwith 1-bromo-2-methoxyethane, stirred and then purified to obtain6-(2-methoxyethoxy)quinoline as a yellow oil. F+: 220.

REFERENCE EXAMPLE E2

A DMSO solution of 7-hydroxyindolin-2-one was mixed withN-(2-chloroethyl)-N,N-diethylamine hydrochloride and potassiumcarbonate, stirred at room temperature for 30 minutes and then stirredat 50° C. for 30 minutes, and the thus formed substance was purified toobtain 7-[2-(diethylamino)ethoxy]indolin-2-one as a yellow oil. F+: 249.

REFERENCE EXAMPLE E3

A THF solution of 6-hydroxyquinoline, 2-(1H-1,2,3-triazol-1-yl)ethanoland triphenylphosphine was mixed with diethyl azodicarboxylate, stirredand then purified to obtain 6-[2-(1H-1,2,3-triazol-1-yl)ethoxy]quinolineas a yellow solid. F+: 241.

REFERENCE EXAMPLE E4

6-Hydroxyquinoline was suspended in 2 M sodium hydroxide aqueoussolution and mixed with tetrabutylammonium hydrogensulfate and1,2-dibromoethane, and the mixture was stirred at 60° C. and thenpurified to obtain 6-(2-bromoethoxy)quinoline as a brown oil. F+: 252,254.

REFERENCE EXAMPLE E5

A DMF solution of2-[(6-hydroxyquinolin-5-yl)methyl]isoindoline-1,3-dione was mixed with1-bromo-2-methoxyethane and cesium carbonate and stirred at 70° C. Thereaction solution was mixed with saturated sodium bicarbonate aqueoussolution, stirred under reflux and then spontaneously cooled to obtain2-{[6-(2-methoxyethoxy)quinolin-5-yl]methyl}isoindoline-1,3-dione as abrown solid. F+: 363.

REFERENCE EXAMPLE F

Piperidin-2-one was added to a DMF solution of 60% NaH and stirred at50° C. After spontaneous cooling, 6-(2-bromoethoxy)quinoline was addedto the reaction solution and stirred, and then the product was purifiedto obtain 1-[2-(quinolin-6-yloxy)ethyl]piperidin-2-one as a yellow oil.F+: 271.

REFERENCE EXAMPLE G

Ethyl 3-oxobutyrate was added to an acetic anhydride solution of6-(2-bromoethoxy)quinoline 1-oxide and stirred at 60° C. The reactionsolution was alkalized and then extracted with ethyl acetate. Theresidue after evaporation of the solvent mixed with 4 M hydrochloricacid and stirred, and then the alkalized reaction solution was extractedwith ethyl acetate. By purifying the thus formed substance, ethyl[6-(2-bromoethoxy)quinolin-2-yl]acetate was obtained. F+: 338, 340.

REFERENCE EXAMPLE H1

An ethyl acetate solution of 6-(2-bromoethoxy)quinoline was mixed with70% m-chloroperbenzoic acid and stirred. The thus formed precipitate wascollected by filtration to obtain 6-(2-bromoethoxy)quinoline N-oxide asa light yellow solid. F+: 268, 270.

REFERENCE EXAMPLE H2

A carbon tetrachloride solution of2-(4-fluoro-3-nitrophenyl)-4,5-dihydro-1,3-oxazole was mixed withN-bromosuccinimide and azobisisobutyronitrile, stirred under reflux andthen subjected to purification to obtain2-(4-fluoro-3-nitrophenyl)-1,3-oxazole as a colorless solid. F−: 208.

Reference Example H3

Under ice-cooling, TEA and sulfur trioxide-pyridine complex were addedto a dichloromethane/DMSO mixed solution of 3-quinolin-6-ylpropan-1-ol,stirred and then subjected to purification to obtain3-quinolin-6-ylpropanal as a brown oil. N2: 2.87-2.93 (2 H, m), 3.15 (2H, t), 7.39 (1 H, dd), 7.57 (1 H, dd), 7.61 (1 H, s), 8.05 (1 H, d),8.08-8.12 (1 H, m), 8.87 (1 H, dd), 9.86 (1 H, t).

REFERENCE EXAMPLE H4

Under ice-cooling, 2-methyl-2-butene, sodium dihydrogenphosphate andsodium chlorite were added to a tert-butanol/water mixed solution of3-quinolin-6-ylpropanal and stirred at the same temperature for 2 hours.This was adjusted to pH 5 to 6 and extracted with chloroform, and thenthe solvent was evaporated to obtain 3-quinolin-6-ylpropionic acid as acolorless solid. F+: 202.

REFERENCE EXAMPLE I1

A THF solution of N,N-diethyl-4-fluoro-3-nitrobenzamide was mixed with1.0 M borane/THF solution and stirred under reflux. The reactionsolution was ice-cooled, mixed with methanol and then stirred. Afterevaporation of the solvent, the resulting residue was mixed with 6 Mhydrochloric acid and stirred at 100° C. After spontaneous cooling, thereaction solution was alkalized and extracted with ethyl acetate. Theresulting organic layer was extracted with 1 M hydrochloric acid, andthe extract was alkalized and extracted with chloroform. By evaporatingthe solvent, N,N-diethyl-N-(4-fluoro-3-nitrobenzyl)amine was obtained asa yellow oil. F+: 227.

REFERENCE EXAMPLE I2

Under ice-cooling, a TFA solution of ethyl4-oxo-4-(2-oxoindolin-5-yl)butyrate was mixed with triethylsilane andstirred at 45° C. and then at room temperature. By purifying theresulting product, ethyl 4-(2-oxoindolin-5-yl)butyrate was obtained as acolorless solid. F+: 248.

REFERENCE EXAMPLE I3

Under ice-cooling, lithium aluminum hydride was added to a THF solutionof ethyl 3-quinolin-7-ylpropionate and stirred at the same temperaturefor 4 hours. Water was added to the reaction solution, and the thusformed precipitate was removed by filtration. The filtrate wasconcentrated, and the resulting residue was subjected to the separationof layers using chloroform and water. By purifying the product from theorganic layer, 3-quinolin-7-ylpropan-1-ol was obtained as a colorlessoil. F+: 230.

REFERENCE EXAMPLE I4

Hydrogenation was carried out under ordinary pressure and at ordinarytemperature, by adding 10% palladium-carbon (Pd—C) to an ethanolsolution of 6-(3-hydroxy-1-propinyl)quinoline. When theoretical amountof hydrogen was absorbed, the catalyst was removed through celite pad.After evaporation of the solvent, the resulting residue was purified bya silica gel column chromatography (to be referred to as SCChereinafter) to obtain 3-quinolin-6-ylpropan-1-ol as a colorless oil.N2: 1.95-2.05 (3 H, m), 2.92 (2 H, t), 3.73 (2 H, t), 7.38 (1 H, dd),7.58 (1 H, dd), 7.61 (1 H, s), 8.03 (1 H, d), 8.09 (1 H, dd), 8.86 (1 H,dd).

REFERENCE EXAMPLE J1

An ethanol solution of 2-bromo-1-(4-chloro-3-nitrophenyl)ethanone wasmixed with thioacetamide, stirred and then subjected to purification toobtain 4-(4-chloro-3-nitrophenyl)-2-methyl-1,3-thiazole as a colorlesssolid. F+: 255.

REFERENCE EXAMPLE J2

A benzene solution of 4-fluoro-3-nitrobenzoic acid was mixed withthionyl chloride and stirred under reflux. After evaporation of thesolvent, the resulting residue was dissolved in dichloromethane, addedto a dichloromethane solution of 2-amino-2-methylpropan-1-ol underice-cooling and then stirred. The thus formed precipitate was removed byfiltration and washed with chloroform. The solvent was evaporated fromthe resulting filtrate and the residue was mixed with thionyl chlorideand stirred. The reaction solution was mixed with diethyl ether toremove diethyl ether-solubilized fraction by decantation and thendiluted with chloroform. By purifying the product from the organiclayer, 2-(4-fluoro-3-nitrophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazolewas obtained as a yellow oil. N2: 1.39 (6 H, s), 4.16 (2 H, s).

REFERENCE EXAMPLE J3

An N-(1,1-dimethoxyethyl)-N,N-dimethylamine solution of4-chloro-3-nitrobenzamide was stirred at 100° C. After evaporation ofthe solvent, hydroxylamine hydrochloride, 1 M sodium hydroxide aqueoussolution, 1,4-dioxane and acetic acid were added to the resultingresidue and stirred at room temperature and then at 90° C. Afterevaporation of the solvent, the resulting residue was mixed with 1 Msodium hydroxide aqueous solution, extracted with chloroform and thenpurified to obtain 5-(4-chloro-3-nitrophenyl)-3-methyl-1,2,4-oxadiazoleas an orange solid. F+: 240.

REFERENCE EXAMPLE K

Under ice-cooling, phosphorus tribromide was added dropwise to adichloromethane solution of 3-quinolin-6-ylpropan-1-ol, and the mixturewas slowly warmed up to room temperature and then stirred under reflux.After spontaneous cooling, this was purified to obtain6-(3-bromopropyl)quinoline as a colorless oil. N2: 2.27 (2 H, qui), 2.99(2 H, t), 3.43 (2 H, t), 7.40 (1 H, dd), 7.59 (1 H, dd), 7.63 (1 H, s),8.06 (1 H, d), 8.13 (1 H, dd), 8.88 (1 H, dd).

REFERENCE EXAMPLE L

A diethylamine solution of 6-bromoquinoline and propargyl alcohol wasmixed with (bistriphenylphosphine)palladium(II) chloride and cuprousiodide and stirred at 45° C. By purifying the thus formed substance fromthe reaction solution, 6-(3-hydroxy-1-propinyl)quinoline was obtained asa colorless solid. F+: 184.

REFERENCE EXAMPLE M1

Concentrated sulfuric acid was added to an ethanol solution of4-chloro-2-methoxy-5-nitrobenzoic acid, and the mixture was stirredunder reflux and then purified to obtain ethyl4-chloro-2-methoxy-5-nitrobenzoate. F+: 260.

REFERENCE EXAMPLE M2

Potassium carbonate and propyl iodide were added to a DMF solution of4-bromo-2-methyl-5-nitrobenzoic acid, and the mixture was stirred andthen purified to obtain propyl 4-bromo-2-methyl-5-nitrobenzoate. E: 301,303.

REFERENCE EXAMPLE N

Under ice-cooling, ethyl succinyl chloride was added to a dichloroethanesuspension of indolin-2-one and aluminum chloride, and the mixture wasstirred at room temperature and then at 50° C. After spontaneouscooling, the reaction solution was poured into ice water, and the thusformed precipitate was collected by filtration to obtain ethyl4-oxo-4-(2-oxoindolin-5-yl)butyrate as brown solid. F+: 262.

REFERENCE EXAMPLE O

A dimethoxyethane solution of 6-bromoindolin-2-one was mixed withtetrakistriphenylphosphine palladium and stirred. The reaction solutionwas mixed with 3-furylboronic acid and an aqueous solution of sodiumcarbonate and stirred under reflux. By purifying the thus formedproduct, 6-(3-furyl)indolin-2-one was obtained as a pink solid. F+: 200.

REFERENCE EXAMPLE P

Pyridine and methanesulfonyl chloride were added to a dichloromethanesolution of ethyl 3-(5-amino-2-methoxyphenyl)propionate, and the mixturewas stirred and then purified to obtain ethyl3-{2-methoxy-5-[(methylsulfonyl)amino]phenyl}propionate as a brownsolid. F+: 302.

REFERENCE EXAMPLE Q

A methanol solution of ethyl3-{2-methoxy-5-[(methylsulfonyl)amino]phenyl}propionate and TEA wasmixed with 90% acrolein and stirred. After evaporation of the solvent,the resulting residue was dissolved in dichloromethane, mixed withtrifluoromethanesulfonic acid, stirred and then subjected topurification to obtain ethyl3-[6-methoxy-1-(methylsulfonyl)-1,2-dihydroquinolin-7-yl]propionate ascolorless solid. N2: 1.26 (3 H, t), 3.83 (3 H, s).

REFERENCE EXAMPLE R

An ethanol solution of ethyl3-[6-methoxy-1-(methylsulfonyl)-1,2-dihydroquinolin-7-yl]propionate wasmixed with potassium hydroxide aqueous solution and stirred. Afteradding 1 M hydrochloric acid to the reaction solution, the solvent wasevaporated. Ethanol and concentrated sulfuric acid were added to theresulting residue, and the mixture was stirred under reflux. Afterspontaneous cooling, the reaction solution was diluted with chloroformand water and alkalized, and then the reaction solution was separatedinto two layers and the product was purified from the resulting organiclayer to obtain ethyl 3-(6-methoxyquinolin-7-yl)propionate as acolorless solid. N2: 1.22 (3 H, t), 4.12 (2 H, q).

REFERENCE EXAMPLE S

Ethyl acetate and saturated sodium bicarbonate aqueous solution wereadded to 4-(4-chloro-3-nitrophenyl)-1,3-thiazole-2-amine hydrobromideand separated. The solvent was evaporated from the organic layer, theresulting residue was dissolved in DMF and added to a DMF solution ofisoamyl nitrite at 70° C., and then the mixture was stirred at the sametemperature. By purifying the thus formed material,4-(4-chloro-3-nitrophenyl)-1,3-thiazole was obtained as a colorless oil.F+: 241.

REFERENCE EXAMPLE T

A carbon tetrachloride solution of ethyl 4-bromo-2-methylbenzoate wasmixed with N-bromosuccinimide and azobisisobutyronitrile, and themixture was stirred under reflux and then purified to obtain ethyl4-bromo-2-(dibromomethyl)benzoate as a colorless solid. N2: 1.42 (3 H,t), 4.40 (2 H, q), 7.99 (1 H, s).

REFERENCE EXAMPLE U

Under ice-cooling, ethyl 4-bromo-2-(dibromomethyl)benzoate and potassiumnitrate were added to concentrated sulfuric acid, and the mixture wasstirred and then purified to obtain ethyl 4-bromo-2-formylbenzoate as acolorless oil. E: 256, 258.

Reference Example V

Under ice-cooling, 4-bromo-2-methylbenzaldehyde and potassium nitratewere added to concentrated sulfuric acid, and the mixture was stirred.The reaction solution was poured into ice water, and the thus formedprecipitate was collected by filtration and then washed to obtain4-bromo-2-methyl-5-nitrobenzaldehyde as a brown solid. N1: 2.74 (3 H,s), 10.24 (1 H, s).

REFERENCE EXAMPLE W

Meldrum's acid was added to methyl orthoformate and stirred at 100° C.for 10 minutes. The reaction solution was mixed with4-bromo-3-methoxyaniline and stirred under reflux and then underspontaneous cooling. The thus formed precipitate was collected byfiltration and then washed to obtain5-{[(4-bromo-3-methoxyphenyl)amino]methylene}-2,2-dimethyl-1,3-dioxane-4,6-dioneas a brown solid. F+: 355, 357.

REFERENCE EXAMPLE X

Diphenyl ether was added to DOW THERM (mfd. by Fluka), and the mixturewas heated to 270° C. This was mixed with5-{[(4-bromo-3-methoxyphenyl)amino]methylene}-2,2-dimethyl-1,3-dioxane-4,6-dione,stirred at the same temperature, spontaneously cooled to 40° C. and thenmixed with petroleum ether, and the thus formed precipitate wascollected by filtration to obtain 6-bromo-7-methoxyquinolin-4(1H)-one asa brown solid. F+: 253, 255.

REFERENCE EXAMPLE Y

A thionyl chloride solution of 6-bromo-7-methoxyquinolin-4(1H)-one wasmixed with DMF and stirred under reflux. The solvent was evaporated, theresulting residue was mixed with chloroform and toluene, and thesolvents were again evaporated. By crystallizing the resulting residuefrom diethyl ether, 6-bromo-4-chloro-7-methoxyquinoline was obtained asa colorless solid. F+: 271, 273.

REFERENCE EXAMPLE Z

Under ice-cooling, phthalimide, triphenylphosphine and diethylazodicarboxylate were added to a THF/DMF mixed solution of(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methanol, and the mixture wasstirred at the same temperature and then subjected to purification toobtain2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]isoindoline-1,3-dioneas colorless solid. F+: 294.

REFERENCE EXAMPLE AA1

tert-Butyl 2-(1-oxidopyridin-4-yl)ethylcarbamate was added to 4 Mhydrogen chloride/ethyl acetate solution and stirred at roomtemperature. The thus formed precipitate was collected by filtration andwashed with ethyl acetate to obtain 2-(1-oxidopyridin-4-yl)ethylamine asa yellow solid. F+: 139.

REFERENCE EXAMPLE AA2

Hydrazine monohydrate was added to an ethanol solution of2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]isoindoline-1,3-dione,and the mixture was stirred under reflux. After spontaneous cooling, thethus formed precipitate was removed through celite, and the filtrate wasconcentrated. Chloroform was added to the resulting residue, theinsoluble matter was removed by filtration and then the filtrate wasconcentrated to obtain(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methylamine as a brown oil. F+:164.

REFERENCE EXAMPLE BB

Dimethyl malonate was slowly added dropwise to a DMSO suspension of 60%NaH, and then the mixture was stirred at 100° C. After cooling down toroom temperature, this was mixed withN-(2,5-dichloro-4-nitrophenyl)acetamide and stirred at the sametemperature and then at 100° C. The thus formed product was purified andthen crystallized from ethyl acetate to obtain dimethyl[5-(acetylamino)-4-chloro-2-nitrophenyl]malonate as a colorless solid.F+: 344.

REFERENCE EXAMPLE CC1

Anhydrous lithium chloride and water were added to a DMSO solution ofdimethyl [5-(acetylamino)-4-chloro-2-nitrophenyl]malonate, and themixture was stirred at 100° C. After spontaneous cooling, the reactionsolution was poured into a mixed solution of ethyl acetate and saturatedbrine and extracted with ethyl acetate. The resulting organic layer waswashed and then concentrated, and the thus obtained crude crystals wererecrystallized from methanol to obtain methyl[5-(acetylamino)-4-chloro-2-nitrophenyl]acetate as a colorless solid. F:286.

REFERENCE EXAMPLE CC2

A 6 M hydrochloric acid solution of diethyl(4-formyl-2-nitrophenyl)malonate was stirred under reflux. The reactionsolution was ice-cooled, and then the thus formed precipitate wascollected by filtration and washed to obtain(4-formyl-2-nitrophenyl)acetic acid. F+: 210.

REFERENCE EXAMPLE DD

Reduced iron was added to an acetic acid solution of methyl[5-(acetylamino)-4-chloro-2-nitophenyl]acetate, and the mixture wasstirred at 100° C., After spontaneous cooling, the reaction solution wasfiltered through celite and washed with DMF. The filtrate wasconcentrated and then mixed with water, and the thus formed precipitatewas collected by filtration and washed with water to obtainN-(6-chloro-2-oxoindolin-5-yl)acetamide as a colorless solid. F+: 225.

REFERENCE EXAMPLE EE

Tetrahydrofuran-2-ylmethylamine was added to a toluene solution ofquinoline-7-carbaldehyde, and the mixture was stirred under reflux usinga Dean-Stark apparatus. The solvent was evaporated, and the resultingresidue was dissolved in methanol, mixed with sodium borohydride andthen stirred. After evaporation of the solvent, the resulting residuewas dissolved in THF, mixed with di-tert-butyl dicarbonate and thenstirred at 70° C. After evaporation of the solvent, the resultingresidue was purified by SCC to obtain tert-butylquinolin-7-ylmethyl(tetrahydrofuran-2-ylmethyl)carbamate as a colorlessoil. F+: 343.

Reference Example FF

Diethylamine and sodium triacetoxyborohydride were added to a1,2-dichloroethane solution of ethyl 3-bromo-2-formylbenzoate, and themixture was stirred. After purification, ethyl3-bromo-2-(diethylaminomethyl)benzoate was obtained as a colorless oil.F+: 314, 316.

The reference example compounds shown in Tables 2 to 5 were obtained inthe same manner as the case of the aforementioned reference examples.

EXAMPLE 1

Under ice-cooling, benzoyl chloride (0.3 ml) was added to a chloroform(25 ml) solution of 6-[2-(1H-1,2,3-triazol-1-yl)ethoxy]quinoline N-oxide(510 mg), and the mixture was stirred at the same temperature for 30minutes. Next. indolin-2-one (265 mg) was added thereto and heated at90° C. under reflux for 8 hours. After spontaneous cooling, saturatedsodium bicarbonate aqueous solution and ethyl acetate were added theretoand stirred for 30 minutes. The thus formed precipitate was collected byfiltration and washed with ethyl acetate. On the other hand, organiclayer of the mother liquor was concentrated, and the thus formedprecipitate was collected by filtration and washed with ethyl acetate.The two precipitates were combine and recrystallized from ethanol toobtain 111 mg of3-{6-[2-(1H-1,2,3-triazol-1-yl)ethoxy]quinolin-2(1H)-ylidene}indolin-2-oneas a red solid.

EXAMPLE 2

A dichloromethane (20 ml) solution of ethyl quinoline-7-carboxylate(3.07 g) was mixed with m-chloroperbenzoic acid (3.3 g) and stirred atroom temperature for 1 hour. After evaporating the solvent, theresulting residue was collected by filtration and washed with ethylacetate. The thus obtained solid matter was dissolved in aceticanhydride (30 ml), mixed with indolin-2-one (3.1 g) and then stirred at55° C. for 12 hours. After evaporation of the solvent, ethanol was addedand the thus formed precipitate was collected by filtration. Byrecrystallizing the thus obtained crude crystals from ethanol, 65 mg ofethyl 2-(2-oxoindolin-3-ylidene)-1,2-dihydroquinoline-7-carboxylate wasobtained as a red solid.

EXAMPLE 3

By the same method of Example 1, (a) 234 mg of2-(2-oxoindolin-3-ylidene)-1,2-dihydroquinoline-4-carbaldehyde wasobtained as a red solid from indolin-2-one (2.11 g) andquinoline-4-carbaldehyde 1-oxide (2.12 g). The crystallization motherliquor was concentrated, the resulting residue was purified by an SCC(elution with chloroform-methanol), and then the thus obtained solidmatter was collected by filtration and recrystallized from ethanol toobtain (b) 55 mg of3-(4-diethoxymethylquinolin-2(1H)-ylidene)indolin-2-one as a brownsolid.

EXAMPLE 4

3-[6-(2-Bromoethoxy)quinolin-2(1H)-ylidene]indolin-2-one (1.86 g) wassuspended in acetonitrile (100 ml), and the suspension was mixed withmorpholine (2.11 g) and stirred at 80° C. for 4 hours. After spontaneouscooling, the reaction solution was mixed with saturated sodiumbicarbonate aqueous solution and saturated brine and extracted withchloroform. The resulting organic layer was dried with anhydrous sodiumsulfate, and then the solvent was evaporated. The resulting residue waspurified by an SSC (elution with methanol-ethylacetate-28% aqueousammonia), and the thus obtained solid matter was recrystallized fromethanol to obtain 960 mg of3-[6-(2-morpholin-4-ylethoxy)quinolin-2(1H)-ylidene]indolin-2-one as ared solid.

EXAMPLE 5

Acetic acid (0.99 ml) was added to a dichloroethane (35 ml) solution of2-(2-oxoindolin-3-ylidene)-1,2-dihydroquinoline-6-carbaldehyde (0.5 g)and 2-morpholin-4-ylethylamine (0.91 ml), and the mixture was stirred atroom temperature for 2 hours. The reaction solution was mixed withsodium triacetoxyborohydride (1.1 g) and stirred at room temperature for13 hours. The reaction solution was mixed with saturated sodiumbicarbonate aqueous solution and extracted with dichloroethane. Theresulting organic layer was washed with water and saturated brine anddried with anhydrous magnesium sulfate, and then the solvent wasevaporated. After purifying the resulting residue by an SSC (elutionwith chloroform), the thus obtained solid matter was collected byfiltration and washed with ethyl acetate to obtain 168 mg of3-(6-{[(2-morphilin-4-ylethyl)amino]methyl}quinolin-2(1H)-ylidene)indolin-2-oneas an orange solid.

EXAMPLE 6

Titanium tetraisopropoxide (0.68 ml) was added to a dichloroethane (3ml) solution of2-(2-oxoindolin-3-ylidene)-1,2-dihydroquinoline-6-carbaldehyde (0.6 g),N-(2-methoxyethyl)-N-methylamine (0.89 ml), and the mixture was stirredat room temperature for 1 hour. After ice-cooling, the reaction solutionwas mixed with sodium triacetoxyborohydride (1.32 g) and stirred at roomtemperature for 1.5 hours. The reaction solution was mixed withsaturated sodium bicarbonate aqueous solution and extracted withdichloroethane. The resulting organic layer was washed with water andsaturated brine and dried with anhydrous magnesium sulfate, and then thesolvent was evaporated. After purifying the resulting residue by an SSC(elution with chloroform), the thus obtained solid matter was collectedby filtration and washed with ethyl acetate to obtain 114 mg of3-(6-{[N-(2-methoxyethyl)-N-methylamino]methyl}quinolin-2(1H)-ylidene)indolin-2-oneas a red solid.

EXAMPLE 7

Pyrrolidine (64 mg) was added to a mixed solution of ethanol (3 ml) andchloroform (3 ml) containing3-[6-(oxiran-2-ylmethoxy)quinolin-2(1H)-ylidene]indolin-2-one (100 mg),and the mixture was stirred at 40° C. for 1.5 hours. After spontaneouscooling, the solvent was evaporated. After purifying the resultingresidue by an SSC (elution with chloroform-methanol-28% aqueousammonia), the thus obtained solid matter was recrystallized from2-propanol to obtain 9 mg of3-[6-(2-hydroxy-3-pyrrolidin-1-ylpropoxy)quinolin-2(1H)-ylidene]indolin-2-oneas an orange solid.

EXAMPLE 8

Morpholine (0.088 ml) was added to a DMF (10 ml) solution of{[2-(2-oxoindolin-3-ylidene)-1,2-dihydroquinolin-6-yl]oxy}acetic acid(280 mg), 1-hydroxybenzotriazole (79 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (225 mg),and the mixture was stirred at room temperature for 3 days. The reactionsolution was poured into water, and the thus formed precipitate wascollected by filtration and then washed with successive water andethanol to obtain 253 mg of3-[6-(2-morpholin-4-yl-2-oxoethoxy)quinolin-2(1H)-ylidene]indolin-2-oneas a red solid.

EXAMPLE 9

Under ice-cooling, TEA (0.3 ml) and bromoacetic acid bromide (0.15 ml)were added to an acetonitrile (10 ml) suspension of3-[6-aminoquinolin-2(1H)-ylidene]indolin-2-one (142 mg), and the mixturewas stirred at room temperature. This was mixed with saturated sodiumbicarbonate aqueous solution and chloroform and stirred at roomtemperature for 30 minutes. The thus formed precipitate was collected byfiltration and washed with chloroform to obtain a red solid matter (196mg). The thus obtained red solid matter was suspended in acetonitrile(20 ml), mixed with morpholine (413 mg) and then stirred at 70° C. for 2hours. After spontaneous cooling, the reaction solution was mixed withsaturated sodium bicarbonate aqueous solution and acetonitrile andstirred at room temperature for 30 minutes. The thus formed precipitatewas collected by filtration and washed with acetonitrile to obtain areddish black solid matter. The thus obtained reddish black solid matterwas purified by an SCC (elution with methanol-ethylacetate-chloroform-28% saturated aqueous ammonia), and the thus obtainedsolid matter was washed with ethanol to obtain 72 mg of2-morpholin-4-yl-N-[2-(2-oxoindolin-3-ylidene)-1,2-dihydroquinolin-6-yl]acetamideas a red solid.

EXAMPLE 10

A DMF (50 ml) solution of 3-[6-nitroquinolin-2(1H)-ylidene]indolin-2-one(1.13 g) was mixed with 10% Pd—C (57 mg), and the mixture was stirredunder an atmosphere of hydrogen at room temperature for 17 hours. Thereaction solution was filtered through celite, and the filtrate wasmixed with saturated brine and extracted with ethyl acetate. The organiclayer was dried with anhydrous sodium sulfate and then the solvent wasevaporated. The resulting residue was purified by an SCC (elution withmethanol-chloroform-ethyl acetate-28% aqueous ammonia), and the thusobtained solid matter was washed with boiling ethanol to obtain 463 mgof 3-[6-aminoquinolin-2(1H)-ylidene]indolin-2-one as a red solid.

EXAMPLE 11

A chloroform (20 ml) solution of3-[6-(2-(thiomorphin-4-ylethoxy)quinolin-2(1H)-ylidene)indolin]-2-one(690 mg) was mixed with m-chloroperbenzoic acid (414 mg) and stirred atroom temperature for 2 hours. The thus formed precipitate was collectedby filtration and recrystallized from methanol to obtain 12 mg of3-{6-[2-(1,4-dioxidothiomorpholin-4-yl)ethoxy]quinolin-2(1H)-ylidene}indolin-2-oneas an orange solid.

EXAMPLE 12

Under ice-cooling, an ethanol (1 ml) solution of tert-butyl4-{[2-(2-oxoindolin-3-ylidene)-1,2-dihydroquinoline-6-yl]carbonyl}piperadin-1-ylcarboxylate(155 mg) was mixed with 4 M hydrogen chloride/ethyl acetate solution (5ml) and stirred at the same temperature for 2 hours. After concentrationof the reaction solution, the resulting residue was collected byfiltration and washed with hot ethanol to obtain 122 mg of3-[6-(piperadine-1-carbonyl)quinolin-2(1H)-ylidene]indolin-2-onehydrochloride as an orange solid.

EXAMPLE 13

Hydrazine hydrochloride (6.5 mg) was added to an ethanol (10 ml)solution of2-{[6-(2-methoxyethoxy)-2-(2-oxoindolin-3-ylidene)-1,2-dihydroquinolin-5-yl]methyl}isoindoline-1,3-dione(20 mg), and the mixture was stirred at 100° C. for 5 hours. Afterspontaneous cooling, the resulting filtrate through celite wasconcentrated. The resulting residue was dissolved in ethanol (2 ml),mixed with 4 M hydrogen chloride/ethyl acetate solution under icecooling, and then stirred at the same temperature for 15 minutes. Afterevaporation of the solvent, the resulting residue was collected byfiltration and washed with hot 2-propanol to obtain 5 mg of3-[5-aminomethyl-6-(2-methoxyethoxy)quinolin-2(1H)-ylidene]indolin-2-onehydrochloride as a red solid.

EXAMPLE 14

An methanol (10 ml) suspension of2-(2-oxoindolin-3-ylidene)-1,2-dihydroquinoline-6-ylmethyl benzoate (200mg) was mixed with 1 M sodium hydroxide aqueous solution (4 ml) andstirred under heating at 70° C. for 15 minutes. After spontaneouscooling, this was mixed with brine and extracted with ethyl acetate. Theresulting organic layer was dried with anhydrous sodium sulfate and thenconcentrated, and the thus obtained residue was purified by an SCC(elution with methanol-ethyl acetate-28% aqueous ammonia). Byrecrystallizing the thus obtained solid matter from ethanol, 24 mg of3-(6-hydroxymethylquinolin-2(1H)-ylidene)indolin-2-one was obtained as ared solid.

EXAMPLE 15

A methanol (5 ml)/THF (10 ml) mixed solution of3-[6-(piperidin-4-ylmethoxy)quinolin-2(1H)-ylidene]indolin-2-onehydrochloride (190 mg) was mixed with 35% formalin (0.08 ml) and sodiumcyanoborohydride (35 mg) and stirred at room temperature for 3 hours.The reaction solution was mixed with saturated sodium bicarbonateaqueous solution, and the thus formed precipitate was collected byfiltration and washed with water. The thus obtained solid matter waspurified by an SCC (elution with chloroform-ethyl acetate-methanol-28%aqueous ammonia). The thus obtained solid matter was collected byfiltration and washed with hot ethanol to obtain 30 mg of3-{6-[(1-methylpiperidin-4-yl)methoxy]quinolin-2(1H)-ylidene}indolin-2-oneas a red solid.

EXAMPLE 16

A xylene (15 ml) suspension of3-[6-aminoquinolin-2(1H)-ylidene]indolin-2-one (103 mg) was mixed with3-pyridyl isocyanate (162 mg) and heated at 130° C. under reflux. Thethus formed precipitate was collected by filtration; heated under refluxin methanol (25 ml) and then filtered while hot, thereby obtaining 48 mgof1-[2-(2-oxoindolin-3-ylidene)-1,2-dihydroquinolin-6-yl]-3-(pyridin-3-yl)ureaas a red solid.

EXAMPLE 17

A DMF (10 ml) solution of ethyl quinolin-2-ylacetate (860 mg) was mixedwith 60% NaH (320 mg) and stirred at room temperature for 10 minutes.Next, this was mixed with ethyl 4-fluoro-3-nitrobenzoate (746 mg) underice-cooling and then stirred at the same temperature for 30 minutes. Thereaction solution was poured into ice water, acidified by adding 1 Mhydrochloric acid aqueous solution and then extracted with ethylacetate. The resulting organic layer was washed with brine, dried overanhydrous sodium sulfate and then concentrated. The resulting residuewas mixed with acetic acid (20 ml) and reduced iron (800 mg) and stirredat 100° C. for 1 hour. The insoluble matter was removed by filtrationand washed with DMF. The mother liquor was mixed with ethyl acetate andwashed with water and brine in that order, and then the organic layerwas dried over anhydrous sodium sulfate and concentrated. By washing theresulting residue with methanol, 274 mg of ethyl3-[quinolin-2(1H)-ylidene]indolin-2-one-carboxylate was obtained as ared solid.

EXAMPLE 18

Dimethylamine hydrochloride (1.6 g) was added to a pyridine (15 ml)solution of ethyl (5-fluoro-2-nitrophenyl)(quinolin-2(1H)-ylidene)actate, and the mixture was stirred at 100° C. for 4 hours.After spontaneous cooling, this was diluted with ethyl acetate andwashed with water and brine. The resulting organic layer was dried overanhydrous magnesium sulfate, and then the solvent was evaporated. Theresulting residue was dissolved in acetic acid (10 ml), mixed withreduced iron (200 mg) and then stirred at 100° C. for 2 hours. Afterspontaneous cooling, the reaction solution was filtrated through celiteand washed with methanol. After concentration of the filtrate, theresulting residue was dissolved in chloroform and washed with water andbrine. The resulting organic layer was dried with anhydrous magnesiumsulfate, and then the solvent was evaporated. The resulting residue waspurified by an SCC (elution with ethyl acetate-hexane), and the thusobtained solid matter was collected by filtration and washed with ethylacetate to obtain 15 mg of5-dimethylamino-3-quinolin-2(1H)-ylideneindolin-2-one as a red solid.

EXAMPLE 19

Quinoline 1-oxide (214 mg) was added to an acetic anhydride (10 ml)solution of 6-methoxyindolin-2-one (200 mg), and the mixture was stirredat 50° C. for 5 hours. After spontaneous cooling, this was poured intoice water and extracted with ethyl acetate. The resulting organic layerwas washed with successive, saturated sodium bicarbonate aqueoussolution, water, and brine and dried over anhydrous magnesium sulfate,and then the solvent was evaporated. The resulting residue was purifiedby an SCC (elution with chloroform) and then recrystallized from diethylether. The thus obtained crystals were collected by filtration andwashed with chloroform to obtain 30 mg of6-methoxy-3-quinolin-2(1H)-ylideneindolin-2-one as a red solid.

EXAMPLE 20

Under ice-cooling, 60% NaH (96 mg) was added to a THF (10 ml) solutionof ethyl quinolin-2-ylacetate (516 mg) and1-(4-chloro-3-nitrophenyl)ethanone (400 mg), and the mixture was stirredat room temperature for 2 hours. The reaction solution was diluted withethyl acetate and washed with water and brine. The resulting organiclayer was dried with anhydrous magnesium sulfate, and then the solventwas evaporated. The thus obtained residue was dissolved in methanol (10ml), mixed with hydroxylamine hydrochloride (168 mg) and then stirred at50° C. for 18 hours. After evaporation of the solvent, the resultingresidue was dissolved in acetic acid (20 ml), mixed with reduced iron(600 mg) and then stirred at 50° C. for 18 hours. The reaction solutionwas subjected to celite filtration and washed with ethyl acetate. Theresulting filtrate was washed with successive, water, 1 M sodiumhydroxide aqueous solution, and brine, the resulting organic layer wasdried over anhydrous magnesium sulfate, and then the solvent wasevaporated. The resulting residue was collected by filtration and washedwith 2-propanol. By recrystallizing the thus obtained crude crystalsfrom DMF, 250 mg of6-(1-methoxyiminoethyl)-3-quinolin-2(1H)-ylideneindolin-2-one wasobtained as a red solid.

EXAMPLE 21

Reduced iron (50 mg) was added to an acetic acid (5 ml) solution of6-acetyl-1-hydroxy-3-quinolin-2(1H)-ylideneindolin-2-one (96 mg), andthe mixture was stirred at 100° C. for 1 hour. The reaction solution wasfiltered through celite and the filtrate was concentrated. Byrecrystallizing the resulting residue from DMF, 35 mg of6-acetyl-3-quinolin-2(1H)-ylideneindolin-2-one was obtained as an orangesolid.

EXAMPLE 22

A methanol (5 ml) solution of acetic2-oxo-3-quinolin-2(1H)-ylideneindoline-5-carboxylic anhydride (234 mg)was mixed with 1 M sodium hydroxide aqueous solution (2 ml), and themixture was stirred at room temperature for 10 minutes. The reactionsolution was acidified by adding 1 M hydrochloric acid, and then thethus formed precipitate was collected by filtration and washed withdiethyl ether and water. By recrystallizing the thus obtained crudecrystals from DMF, 65 mg of2-oxo-3-quinolin-2(1H)-ylideneindoline-5-carboxylic acid was obtained asan orange solid.

EXAMPLE 23

Ethyl 4-(2-oxo-3-quinolin-2(1H)-ylideneindolin-5-yl)butyrate (350 mg)was suspended in 6 M hydrochloric acid (15 ml) and stirred under refluxfor 5 hours. After spontaneous cooling, the thus formed precipitate wascollected by filtration and washed with water to obtain 97 mg of4-(2-oxo-3-quinolin-2(1H)-ylideneindolin-5-yl)butyric acid as an orangesolid.

EXAMPLE 24

An acetic acid (10 ml) solution of5-benzyloxy-3-quinolin-2(1H)-ylideneindolin-2-one (183 mg) was mixedwith 5% Pd—C (100 mg), and the mixture was subjected to 18 hours ofhydrogenation at room temperature under 4 atmospheric pressure. Thereaction mixture was filtered through celite, and the filtrate wasconcentrated. The thus obtained solid matter was collected by filtrationand washed with methanol to obtain 68 mg of5-hydroxy-3-quinolin-2(1H)-ylideneindolin-2-one as a red solid.

EXAMPLE 25

To a DMF (20 ml) solution of benzyl2-oxo-3-quinolin-2(1H)-ylideneindoline-6-carboxylate (120 mg) was added5% Pd—C (50 mg), and the mixture was subjected to 3 days ofhydrogenation at room temperature under 1 atmospheric pressure. Thereaction solution was mixed with DMF (80 ml), filtered through celitewhile hot, and the filtrate was concentrated. The thus obtained solidmatter was collected by filtration and washed with methanol to obtain 44mg of 2-oxo-3-quinolin-2(1H)-ylideneindoline-6-carboxylic acid as a redsolid.

EXAMPLE 26

TFA (5 ml) was added to a mixed solution of dichloromethane (5 ml) andTHF (5 ml) containing tert-butyl2-(2-oxo-3-quinolin-2(1H)-ylideneindolin-6-yl)-1H-pyrrole-1-carboxylate(93 mg), and the mixture was stirred at room temperature for 18 hours.After evaporation of the solvent, methanol was added to the resultingresidue, and the thus formed crystals were collected by filtration toobtain 56 mg of 6-(1H-pyrrol-2-yl)-3-quinolin-2(1H)-ylideneindolin-2-oneas a red solid.

EXAMPLE 27

Thioacetamide (90 mg) was added to a DMF (10 ml) solution of5-(2-chloroacetyl)-3-quinolin-2(1H)-ylideneindolin-2-one (337 mg), andthe mixture was stirred at 100° C. for 1 hour. The reaction solution waspoured into water, and the thus formed precipitate was collected byfiltration and washed with water and ethanol. The thus obtained solidmatter was dissolved in a chloroform-methanol mixed solution and washedwith water and brine, the resulting organic layer was dried withanhydrous magnesium sulfate, and then the solvent was evaporated. Byrecrystallizing the resulting residue from DMF, 68 mg of5-(2-methyl-1,3-thiazol-4-yl)-3-quinolin-2(1H)-ylideneindolin-2-one wasobtained as a red solid.

EXAMPLE 28

Imidazole (144 mg) was added to a DMF (20 ml) solution of5-(4-chlorobutanoyl)-3-quinolin-2(1H)-ylideneindolin-2-one (350 mg), andthe mixture was stirred at 55° C. for 5 days. After spontaneous cooling,the reaction solution was poured into ice water, and the thus formedprecipitate was collected by filtration and washed with water. The justdescribed precipitate was purified by an SCC (elution withchloroform-methanol), and the thus obtained solid matter was collectedby filtration and washed with diethyl ether to obtain 61 mg of5-(4-hydroxybutanoyl)-3-quinolin-2(1H)-ylideneindolin-2-one as an orangesolid.

EXAMPLE 29

Ethoxylamine hydrochloride (98 mg) was added to a methanol (5 ml)solution of ethyl(4-formyl-2-nitrophenyl)[6-(2-morpholin-4-ylethoxy)quinolin-2(1H)-ylidene]acetate(354 mg), and the mixture was stirred at room temperature for 1 hour.After evaporation of the solvent, the resulting residue was dissolved inacetic acid (10 ml), mixed with reduced iron (200 mg) and then stirredat 100° C. for 1 hour. After spontaneous cooling, this was mixed withchloroform-2-propanol (3:1) mixed solution and 1 M sodium hydroxideaqueous solution, filtrated through celite and then washed withchloroform. The resulting filtrate was subjected to the separation oflayers, and the organic layer was washed with water and then with brine.The organic layer was dried with anhydrous magnesium sulfate, and thenthe solvent was evaporated. The resulting residue was purified by an SCC(elution with chloroform-methanol). The thus obtained solid matter wasdissolved in methanol (5 ml), mixed with 4 M hydrogen chloride/ethylacetate solution (0.25 ml) and then stirred at room temperature for 10minutes. The thus formed precipitate was collected by filtration andwashed with methanol to obtain 58 mg of3-[6-(2-morpholin-4-ylethoxy)quinolin-2(1H)-ylidene]-2-oxoindoline-6-carbaldehydeO-ethyloxime hydrochloride as a red solid.

EXAMPLE 30

Under ice-cooling, 60% NaH (80mg) was added to a DMF (5 ml) solution ofethyl quinolin-2-ylacetate (215 mg) and1-(4-chloro-3-nitrophenyl)ethanone (200 mg), and the mixture was stirredat the same temperature for 1 hour. The reaction solution was pouredinto water and acidified using 1 M hydrochloric acid, and then the thusformed precipitate was collected by filtration and washed with water.The thus obtained solid matter was dissolved in acetic acid (10 ml),mixed with 5% Pd—C (50 mg) and then subjected to 18 hours ofhydrogenation at room temperature under 3.5 atmospheric pressure. Thereaction mixture was filtered through celite and washed with DMF, andthe filtrate was concentrated. The thus obtained residue was collectedby filtration and washed with ethanol. By recrystallizing the thusobtained crude crystals from DMF, 70 mg of6-acetyl-1-hydroxy-3-quinolin-2(1H)-ylideneindolin-2-one.

The Example compounds described in the following Tables 6 to 20 wereobtained in the same manner as in the aforementioned Examples.Structures and physicochemical properties of the reference examplecompounds and Example compounds are respectively shown in the followingTables 2 to 5 and 6 to 20. In addition, the compounds whose chemicalstructures are shown in Tables 21 and 22 can be produced easily inalmost the same manner as the methods of the aforementioned Examples orproduction methods, or by applying thereto slight modifications obviousto those skilled in the art.

Abbreviations in the tables respectively indicate, Rex: referenceexample number; Ex: Example number; Co: compound number; Str: structure;Sal: salt (blank: free base or free acid; Su: succinate; HCl:hydrochloride); Sy: production method (each numeral shows the number ofthe aforementioned Example, indicating that said compound was producedby the same method of this aforementioned Example) and Rsy: referenceexample production method (each numeral shows the number of theaforementioned Reference Example, indicating that said compound wasproduced by the same method of this aforementioned Reference Example);Dat: physicochemical property; Me: methyl; Et: ethyl; Pr: n-propyl; iPr:isopropyl; cPr: cyclopropyl; Bu: n-butyl; iBu: isobutyl; cHex:cyclohexyl; Ph: phenyl; Bz: benzoyl; Bn: benzyl; Ac: acetyl; Ms:methylsulfonyl; Thie3: 3-thienyl; Py2: 2-pyridyl; Py3: 3-pyridyl; Py4:4-pyridyl; Thia4: 4-tiazolyl; Pip1: 1-piperidyl; Pip2: 2-piperidyl;Pip3: 3-piperidyl; Pip4: 4-piperidyl; Morp: morpholino; Pipera:1-piperazinyl; Pim: 4-methyl-1-piperazinyl; Im1: 1-imidazolyl; Im2:2-imidazolyl Fu3: 3-furyl; Pyrr2: 2-pyrrolyl; Pyrim2: 2-pyrimidinyl;Pyrim5: 5-pyrimidinyl; Pyra: 2-pyrazinyl; Tet: 2H-tetrazol-5-yl; Thiom:thiomorpholino; Boc: tert-butoxycarbonyl; and Pht: phthalimid-2-yl. Inthis case, the numeral before each substituent indicates its substitutedposition, and when two or more of R¹ or R² group are present, they arelisted in the table together with their substituted positions. Forexample, 4-OMe-5,6-F₂ indicates that methoxy is substituted at the4-position, and F atom at the 5- and 6-positions. TABLE 2 Rex Rex RsyStr Dat Rsy Str Dat 1 A1

F+: 355 2 A1

F−: 363 3 A1

F+: 494 4 A1

F+: 362 5 B1

F+: 284 6 B1

F+: 241

TABLE 3

Rex Rex Rsy (R¹)n Dat Rsy (R¹)n Dat  7 6-O(CH₂)₃CO₂Et F+: 260  86-OCH₂-(1-Boc-Pip4) F+: 343 E2 E3  9 6-OCH₂CO₂Et F+: 232 10 6-O(CH₂)₃BrN2: 2.40(2H, qui), 3.66(2H, t), E2 E4 4.24(2H, t), 7.10(1H, d), 7.33-7.39(2H, m), 8.01(1H, d), 8.04 (1H, dd), 8.77(1H, dd) 116-OMe-7-(CH₂)₃OH F+: 218 12 6-O(CH₂)₄Br N2: 1.99-2.17(4H, m), 3.53(2H,I3 E4 t), 4.14(2H, t), 7.10(1H, d), 7.35-7.42(2H, m), 7.97(1H, d),8.10(1H, dd), 8.70(1H, dd) 13 6-(CH₂)₃OH-7-OMe F+: 218 14 6-O(CH₂)₅BrN2: 1.68(2H, qui), 1.85-2.02(4H, I4 E4 m), 3.46(2H, t), 4.09(2H, t),7.05(1H, d), 7.34(1H, dd), 7.37 (1H, dd), 7.99(1H, d), 8.07(1H, dd),8.76(1H, dd) 15 4-Cl-6-C≡CCH₂OH- F+: 248 16 6-(CH₂)₃Br-7-OMe N2:2.23(2H, qui), 2.95(2H, t), L 7-OMe K 3.44(2H, t), 3.98(3H, s), 7.27(1H, t), 7.42(1H, s), 7.57(1H, s), 8.04(1H, dd), 8.79(1H, dd) 177-(CH₂)₂CO₂Et F+: 230 18 6-OMe-7-(CH₂)₃Br F+: 280, 282 R K

TABLE 4

Rex Rex Rsy (R¹)n Dat Rsy (R¹)n Dat 19 H1

F+: 257 20 H1 4-CH₂OBz N2: 5.77(2H, s), 8.60(1H, d), 8.85(1H, dd) 214-(CH₂)₂CO₂H F+: 218 22 4-O(CH₂)₂Br F+: 268, 270 H1 H1 23 6-O(CH₂)₂OMeF+: 220 24 6-O(CH₂)₂NEt₂ F+: 261 H1 C 25 6-O(CH₂)₃CO₂Et F+: 276 266-O(CH₂)₂Br- F+: 298, 300 H1 H1 7-OMe 27 6-OCH₂CO₂Et F+: 248 28 6-CH₂BrF+: 238, 240 H1 H1 29 6-OCH₂(1-Boc-Pip4) F+: 359 30 6-O(CH₂)₃Br F+: 282,284 H1 H1 31 6-(CH₂)₂CO₂H F+: 218 32 6-O(CH₂)₄Br F+: 296, 298 H1 H1 336-(CH₂)₃Br-7-OMe F: 296, 298 34 6-O(CH₂)₅Br F+: 310, 312 H1 H1 356-CH₂OH F+: 176 36 5-O(CH₂)₂Br F+: 268, 270 H1 H1 37 5-CH₂-Pht- F+: 37938 6-OBn N1: 5.26(2H, s), 8.43(1H, br d), H1 6-O(CH₂)₂OMe H1 8.45(1H, d)39 H1

F+: 218 40 H1 6-(CH₂)₃Br N2: 2.27(2H, qui), 3.00(2H, t), 3.42(2H, t),7.29(1H, dd), 7.62(1H, dd), 7.69(1H, s), 8.58(1H, d), 9.39(1H, d),9.56(1H, d) 41 H1

F+: 287 42 H1 7-O(CH₂)₂Br N1: 3.90(2H, t), 4.54(2H, t), 7.35(1H, dd),7.42(1H, dd), 7.90(1H, d), 7.91(1H, s), 8.04(1H, d), 8.57(1H, dd) 434-(CH₂)₂CO₂Et F+: 246 44 6-CHO N1: 7.61(1H, dd), 8.13-8.21(2H, H1 H3 m),8.67(1H, d), 8.64-8.76(2H, m), 10.20-10.23(1H, m)

TABLE 5 Rex Rex Rsy Str Dat Rsy Str Dat 45 V

F−: 358, 360 46 E1

F+: 229 47 C

F+: 345 48 E1

F+: 243 49 E1

F+: 257 50 E1

E: 263, 265 51 E2

F+: 249 52 E2

F+: 249 53 E3

F+: 269 54 E3

F+: 255 55 E4

F+: 216 56 DD

F+: 220 57 I2

F+: 248 58 H2

F+: 223 59 J2

F+: 225 60 I2

F+: 224 61 J2

F+: 225 62 J2

F+: 211 63 J2

F+: 239 64 M1

F+: 287, 289 65 M2

F+: 302, 304 66 M2

F+: 315, 317 67 P

F+: 272 68 N

F+: 262 69 O

F+: 299 70 BB

F+: 369 71 Q

N2: 1.25(3H, t), 2.69(3H, s) 72 BB

F+: 368 73 BB

F+: 312 74 BB

N2: 5.35(1H, s), 10.10(1H, s) 75 CC2

F+: 297 76 DD

F+: 249 77 CC1

N2: 2.96(3H, s), 4.03(2H, s), 7.23(1H, s), 8.69(1H, s) 78 DD

F+: 191 79 DD

F+: 192 88 DD

F+: 240

TABLE 6 (I)

Ex (R¹)n Sal Sy Dat  1

— N1: 4.49(2H, t), 4.84(2H, t), 7.76(1H, d), 8.23(1H, d), 10.53(1H, s),14.43(1H, s); F+: 372  2 7-CO₂Et — F+: 333 3a 4-CHO — N1: 10.66(1H, s),12.60(1H, s), 14.10(1H, s)  3b 4-CH(OEt)₂ — F+: 363  4 6-O(CH₂)₂-Morp —N1: 2.51(4H, t), 2.78(2H, t), 3.59(4H, t), 4.16(2H, t), 10.53(1H, s),14.46(1H, s); F+: 390  5 6-CH₂NH(CH₂)₂-Morp — N1: 3.55(4H, t), 3.78(2H,s), 10.56(1H, s); F+: 403  6 6-CH₂N(Me)(CH₂)₂OMe — N1: 2.19(2H, s),2.25-2.60(4H, m), 3.53(2H, s), 10.57(1H, s), 14.38(1H, s); F+: 361  7

— N1: 1.65-1.71(4H, m), 2.42-2.54(5H, m), 2.64(1H, dd), 3.90-4.00(2H,m), 4.04-4.12(1H, m), 4.93(1H, d), 10.51(1H, s), 14.47(1H, s); F+: 404 8 6-OCH₂CO-Morp — N1: 3.40-3.73(8H, m), 4.92(2H, s), 10.53(1H, s),14.46(1H, s); F: 403  9 6-NHCOCH₂-Morp — F−: 401 10 6-NH₂ — N1: 5.39(2H,s), 10.43(1H, s), 14.52(1H, s); F−: 274 11

— F+: 438 12 6-CO-Pipera HCl — F+: 373 13 5-CH₂NH₂-6-O(CH₂)₂OMe HCl —N1: 3.35(3H, s), 3.72-3.76(2H, m), 4.28-4.33(2H, m), 4.34-4.41(2H, m),10.59(1H, s): F+: 364 14 6-CH₂OH — N1: 4.57(2H, s), 10.57(1H, s),14.40(1H, s); F+: 291 15 6-OCH₂(1-Me-Pip4) — N1: 2.50(3H, s), 3.90(2H,d), 10.51(1H, s), 14.46(1H, s); F+: 388 16 6-NHCONH-Py3 — N1: 10.55(1H,s), 14.42(1H, s); F−: 394 31 6-OCH₂CH₂Br 1 F+: 283, 285 32 2:1 mixtureof 1 N2: 2.44(3H × 2/3, s), 2.57(3H × 1/3, s), 7-Me and 5-Me 10.57(1H,s), 14.37(1H, s); F+: 275 33 6-OCH₂CH₂CH₂Br 1 N1: 2.30(2H, qui),3.71(2H, t), 4.17(2H, t), 10.54(1H, s), 14.46(1H, s) 34 6-O(CH₂)₄Br 1F+: 411, 413 35 6-O(CH₂)₅Br 1 F+: 425, 427 36 6-OBz HCl 1 N1: 10.61(1H,s), 14.39(1H, s); F+: 381

TABLE 7 37 6-OMe HCl 1 N1: 3.85(3H, s), 10.52(1H, s), 14.47(1H, s); F+:291 38 4-Me 1 N2: 2.66(3H, s), 10.55(1H, s), 14.35(1H, s); F+: 275 394-CH₂CH₂CO₂Et 1 N2: 1.17(3H, s), 2.84(2H, t), 3.32(2H, t), 4.09(2H, q),10.55(1H, s), 14.29(1H, s); F+: 361 40 4-CH₂OBz 1 N1: 5.84(2H, s),10.60(1H, s), 14.16(1H, s); F: 394 41 6-O(CH₂)₂-Pim 4 N1: 2.15(3H, s),2.25-2.40(4H, m), 2.45-2.55(4H, m), 2.72(2H, t), 4.15(2H, t), 10.52(1H,s), 14.46(1H, s); F+: 403 42 6-O(CH₂)₃-Morp 4 N1: 1.92(2H, qui),2.35-2.41(4H, m), 2.45(2H, t), 3.58(4H, t), 4.09(2H, t), 10.51(1H, s),14.47(1H, s); F+: 404 43 6-CH₂OBz 1 N1: 5.43(2H, s), 10.61(1H, s),14.35(1H, s); F+: 395 44 6-OCH₂CH₂—NEt₂ Su 1 N1: 1.02(6H, t), 2.39(4H,s), 2.65(4H, q), 2.91(2H, t), 4.13(2H, t), 10.53(1H, s), 14.46(1H, s);F+: 376 45

4 N1: 1.05(6H, d), 1.74(2H, t), 2.71(2H, t), 2.84(2H, d), 3.53-3.60(2H,m), 4.16(2H, t), 10.51(1H, s), 14.46(1H, s); F+: 418 46

4 N1: 1.62(4H, t), 2.57(4H, brt), 2.76(2H, t), 3.86(4H, s), 4.15(2H, t),10.51(1H, s), 14.46(1H, s); F+: 446 47 6-O(CH₂)₄-Morp 4 N1:1.56-1.63(2H, m), 1.74-1.81(2H, m), 2.32-2.35(6H, m), 3.56(4H, t),4.07(2H, t), 10.51(1H, s), 14.46(1H, s); F+: 418 48 6-O(CH₂)₅-Morp 4 N1:1.44-1.50(4H, m), 1.74-1.83(2H, m), 2.27-2.30(2H, m), 2.33(4H, brs),3.56(4H, t), 4.05(2H, t), 10.51(1H, s), 14.46(1H, s); F+: 445 49 6-NO₂ 1E+: 306 50 8-Me 1 E+: 275 51 4-Cl 1

: 295 52 6-OBn 1 N1: 5.19(2H, s), 10.53(1H, s), 14.45(1H, s); F+: 367 53

Su 4 N1: 1.00(3H, d), 1.05(3H, d), 10.52(1H, s), 14.46(1H, s); F+: 44554 6-CH₂-Morp 4 N1: 2.39(4H, brs), 3.54(2H, s), 3.59(4H, t), 10.57(1H,s), 14.38(1H, s); F+: 360 55

4 N1: 1.10(6H, d), 10.52(1H, s), 14.47(1H, s); F+: 416 56 6-Br 1 N1:10.63(1H, s), 14.27(1H, s); F+: 338, 340

TABLE 8 57

4 N1: 10.51(1H, s), 14.46(1H, s); F+: 418 58 6-O(CH₂)₂OMe 19 N1:3.33(3H, s), 3.65-3.74(2H, m), 4.11-4.21 (2H, m), 10.53(1H, s); F+: 33559

19 N1: 1.60-1.80(4H, m), 2.17-2.27(2H, m), 10.52 (1H, s), 14.45(1H, s);F+: 402 60

19 N1: 2.76(1H, td), 2.88(1H, t), 3.38-3.43(1H, m), 3.94(1H, td),4.44(1H, ddd), 10.53(1H, s), 14.46(1H, s) 61 6-O(CH₂)₃CO₂Et 1 F+: 391 626-OCH₂CO₂Et 1 F+: 363 63 5-CH₂Pht-6-O(CH₂)₂OMe 1 F+: 494 646-OCH₂(1-Boc-Pip4) 1 F+: 474 65 6-CO₂H 1 F+: 305 66 6-(CH₂)₂CO₂H 1 N1:2.61(2H, t), 2.91(2H, t), 10.55(2H, s), 12.23 (1H, s), 14.35(1H, s); F+:333 67 6-(CH₂)₃Br-7-OMe 1 F+: 411, 413 68 6-CHO 1 N1: 6.91-7.06(3H, m),7.64(1H, d), 7.68(1H, d), 7.78(1H, d), 8.03(1H, d), 8.09(1H, d),8.28(1H, s), 9.98(1H, s), 10.70(1H, s), 14.29(1H, s) 69 4-(CH₂)₂CO₂H 1N1: 2.61(2H, t), 2.91(2H, t), 10.55(2H, s), 12.23 (1H, s), 14.35(1H, s);F+: 333 70 4-CO₂H 1 F+: 305 71 4-O(CH₂)₂Br 1 F: 382, 384 72 5-NO₂ 1 F−:304 73 6-O(CH₂)₂Cl 1 F+: 339 74 6-OMe-7-(CH₂)₃Br 2 F+: 411, 413 757-(CH₂)₃Br 2 F+: 381, 383 76 7-(CH₂)₂CO₂Et 2 F+: 361 776-OMe-7-(CH₂)₃Morp 4 F+: 418 78 6-O(CH₂)₂(4-OH-Pip1) 4 N1:.1.35-1.44(2H, m), 1.68-1.75(2H, m), 2.15(2H, t), 2.70(2H, t),2.78-2.83(2H, m), 3.41-3.49(1H, m), 4.13(2H, t), 4.53(1H, d), 10.51(1H,s), 14.46(1H, s); F+: 404 79 6-O(CH₂)₂(4-CO₂Et-Pip1) 4 F+: 460 80

4 F+: 438 81

4 F+: 520 82

4 N1: 6.62(1H, t), 8.35(2H, d), 10.52(1H, s), 14.46(1H, s); F+: 467 83

4 F+: 417 84 6-O(CH₂)₂(4-Pip1-Pip1) 4 F+: 471

TABLE 9 85

4 N1: 2.37(2H, t), 2.35-2.50(8H, m), 2.72(2H, t), 3.48(2H, q), 4.14(2H,t), 4.36(1H, t), 10.52(1H, s), 14.46(1H, s); F+: 433 86

4 N1: 2.14(6H, s), 2.28(3H, s), 2.34(2H, dd), 2.48-2.53(2H, m), 2.78(2H,t), 4.13(2H, t), 10.52(1H, s), 14.46(1H, s); F+: 405 87

HCl 4 F+: 431 88

4 N1: 1.5-1.6(1H, m), 1.9-2.1(1H, m), 2.4-2.5(1H, m), 2.6-2.8(4H, m),4.1-4.3(3H, m), 4.6-4.7(1H, m), 10.51(1H, s), 14.46(1H, s); F+: 390 89

4 N1: 2.30(3H, s), 2.5-2.6(2H, m), 2.79(2H, t), 3.4-3.6(2H, m),4.1-4.2(2H, m), 4.37(1H, t), 10.52(1H, s), 14.47(1H, s); F−: 376 90

4 N1: 1.5-1.9(4H, m), 2.3-2.4(1H, m), 2.6-2.7(1H, m), 3.1-3.5(4H, m),4.13(2H, t), 4.39(1H, t), 10.52(1H, s), 14.47(1H, s); F+: 404 91

4 N1: 1.4-1.6(2H, m), 2.11(6H, s), 2.2-2.5(12H, m), 2.72(2H, t),4.15(2H, t), 10.51(1H, s), 14.46(1H, s) F+: 474 92

4 N1: 1.5-1.7(6H, m), 2.2-2.5(12H, m), 2.72(2H, t), 4.15(2H, t),10.51(1H, s), 14.46(1H, s); F+: 500 93 6-O(CH₂)₂(4-CONH₂-Pip1) 4 F+: 43194

N N1: 1.63(2H, qui), 2.29(2H, t), 2.30-2.42(8H, m), 2.72(2H, t),3.21(3H, s), 3.32(2H, t), 4.15(2H, t), 10.52(1H, s), 14.46(1H, s); F+:461 95 6-O(CH₂)₂-Thiom 4 F+: 406 96 6-(CH₂)₃-Morp 4 N1: 1.78(2H, qui),2.30(2H, t), 2.32-2.38(4H, m), 2.69(2H, t), 3.58(2H, t), 10.55(1H, s),14.38(1H, s); F+: 383 97 6-(CH₂)₃-Morp-7-OMe 4 F+: 418 98 6-(CH₂)₃-PimHCl 4 N1: 2.05-2.15(2H, m), 2.76(2H, t), 2.83(3H, s), 3.12-3.85(10H, m),10.58(1H, s), 14.34(1H, s); F+: 401 99 6-(CH₂)₃NEt₂ 4 N1: 0.93(6H, t),1.73(2H, qui), 2.39(2H, t), 2.45(4H, q), 2.66(2H, t), 10.55(1H, s),14.38(1H, s); F+: 374 100 4-O(CH₂)₂-Morp 4 F−: 388 101 7-(CH₂)₃-Morp 4N1: 3.58(4H, t), 10.57(1H, s), 14.36(1H, s); F+: 388 102 7-O(CH₂)₂-Morp4 N1: 2.48-2.52(4H, m), 2.74(2H, t), 3.60(4H, t), 4.26(2H, t), 10.55(1H,s), 14.38(1H, s); F+: 390 103 7-(CH₂)₃NEt₂ 4 N1: 0.94(4H, t), 10.55(1H,s), 14.37(1H, s); F+: 374 104 7-(CH₂)₃-Pim 4 N1: 2.14(3H, s), 10.57(1H,s), 14.36(1H, s); F+: 401

TABLE 10 105 5-O(CH₂)₂-Morp 4 N1: 2.54(4H, t), 2.83(2H, t), 3.60(4H, t),4.27(2H, t), 10.57(1H, s), 14.34(1H, s); F+: 390 106

4 N1: 0.94(12H, d), 2.2-2.3(2H, m), 2.71(2H, t), 2.9-3.0(2H, m),4.15(2H, t), 10.51(1H, s), 14.46(1H, s); F+: 516 107

4 N1: 1.5-1.7(8H, m), 2.3-2.8(16H, m), 2.89(2H, t), 4.12(2H, t),10.51(1H, s), 14.46(1H, s); F+: 514 108

4 N1: 1.55(2H, t), 2.3-2.5(12H, m), 2.72(2H, t), 3.5-3.6(4H, m),4.15(2H, t), 10.51(1H, s), 14.46(1H, s); F+: 516 109

4 N1; 2.3-2.5(12H, m), 2.71(2H, t), 3.5-3.6(4H, m), 4.14(2H, t),10.51(1H, s), 14.46(1H, s); F+: 502 110 6-(CH₂)₃(4-OH-Pip1) 4 F+: 402111

5 N1: 1.49-1.57(1H, m), 1.75-1.82(2H, m), 1.86-1.94(1H, m), 2.14(1H,brs), 2.53-2.57(2H, m), 3.60(1H, q), 3.80(2H, s), 3.89(1H, q), 10.56(1H,s), 14.39(1H, s); F−: 372 112 6-CH₂NH(CH₂)₂OMe 5 N1: 2.33(1H, s),2.66(2H, t), 3.24(3H, s), 3.42(2H, t), 3.78(2H, s), 10.57(1H, s),14.39(1H, s); F+: 348 113

HCl 5 N1: 1.17-1.27(2H, m), 1.68(2H, dd), 1.95-2.05(1H, m), 2.85(2H, s),3.28(2H, td), 3.85(2H, dd), 4.21(2H, s), 10.63(1H, s), 14.31(1H, s); F:387 114

5 N1: 2.66(2H, d), 4.91(1H, t), 10.55(1H, s), 14.38 (1H, s); F: 375 115

5 N1: 1.22-1.37(2H, m), 1.75-1.86(2H, m), 2.58-2.69(1H, m), 10.57(1H,s); F: 373 116

5 N1: 3.70(2H, s), 3.90(1H, qui), 10.57(1H, s), 14.38(1H, s); F: 345 1176-CH₂NH(CH₂)₃OMe 5 N1: 1.70(2H, qui), 3.82(2H, s), 10.58(1H, s),14.38(1H, s); F+: 362 118

5 N1: 1.01(3H, t), 3.79(2H, s), 10.57(1H, s), 14.39 (1H, s); F+: 401 119

5 N1: 0.97(3H, d), 1.64(4H, br), 3.72(1H, d), 3.87 (1H, d), 10.57(1H,s), 14.39(1H, s); F−: 399 120

5 N1: 0.24-0.29(2H, m), 0.36-0.42(2H, m), 1.56-1.62(1H, m),2.30-2.40(4H, m), 2.50-2.58(4H, m), 3.51(2H, s), 10.57(1H, s), 14.38(1H,s); F+: 399 121

5 F: 345 122

5 N1: 1.45-1.58(1H, m), 1.70-2.00(3H, m), 3.80(2H, s), 10.57(1H, s),14.38(1H, s); F+: 374

TABLE 11 123

5 N1: 1.45-1.58 (1H, m), 1.70-2.00(3H, m), 3.79(2H, s), 10.57(1H, s),14.39(1H, s); F+: 374 124

5 N1: 1.53-1.63(2H, m), 1.69-1.73(1H, m), 2.09(2H, d), 2.42(2H, d),2.98-3.14(4H, m), 3.75(2H, s), 10.56(1H, s), 14.38(1H, s); F: 435 1256-CH₂NEt₂ 5 1.00(6H, br), 3.59(2H, s), 10.58(1H, s), 14.38 (1H, s); F:345 126 6-CH₂NHCH₂CO₂Et 5 F+: 376 127

5 F: 373 128 6-CH₂-Morp 5 F+: 360 129

6 N1: 1.72(2H, qui), 2.26(3H, s), 3.66(2H, s), 10.56(1H, s), 14.38(1H,s); F+: 387 130 6-CH₂-(4-CONH₂-Pip1) 6 N1: 1.45-2.25(7H, m), 3.51(2H,s), 10.57(1H, s), 14.38(1H, s); F+: 401 131 6-CH₂-(4-Pyrim2-Pipera) 6N1: 2.40-2.54(4H, m), 3.59(2H, s), 3.72-3.82 (4H, m), 10.58(1H, s),14.39(1H, s); F+: 437 132 6-CH₂-Pim 6 N1: 2.21(3H, s), 2.25-2.60(4H, m),3.53(2H, s), 10.57(1H, s), 14.38(1H, s); F+: 373 133

HCl 6 N1: 2.05-2.15(1H, m), 2.15-2.27(1H, m), 3.68(1H, q), 3.75-3.85(2H,m), 3.89-3.96(2H, m), 4.18(2H, dd), 10.64(1H, s), 14.31(1H, s); F+: 360134 6-CH₂-(4-Et-Pipera) 6 N1: 0.98(3H, t), 2.20-2.60(10H, m), 3.53(2H,s), 10.57(1H, s), 14.38(1H, s); F+: 387 135

HCl 6 N1: 2.05-2.15(1H, m), 2.15-2.27(1H, m), 3.68(1H, q), 3.75-3.85(2H,m), 3.89-3.96(2H, m), 4.18(2H, dd), 10.64(1H, s), 14.31(1H, s); F: 359136 6-CH₂-(4-Pr-Pipera) 6 N1: 0.84(3H, t), 1.35-1.47(2H, m), 3.52(2H,s), 10.56(1H, s), 14.38(1H, s); F+: 401 137 6-CH₂-(3,3-F₂-Pip1) 6 N1:1.8-2.3(4H, m), 2.7-3.3(1H, m), 3.3-3.7(1H, m), 3.64(2H, brs), 4.41(2H,brs), 10.63(1H, s), 14.29(1H, s); F+: 394 138

6 N1: 0.80-0.95(3H, m), 1.10(3H, d), 2.17(3H, s), 3.32(2H, s), 10.57(1H,s), 14.38(1H, s); F+: 401 139

6 N1: 2.7-2.8(4H, m), 3.78(2H, s), 7.27(2H, d), 8.11(2H, d), 10.57(1H,s), 14.38(1H, s); F+: 411 140 6-CH₂-(4-Ac-Pipera) 6 N1: 1.98(3H, s),3.56(2H, s), 10.58(1H, s), 14.38(1H, s); F+: 401 141

6 N1: 2.83-3.03(4H, m), 3.05-3.20(4H, m), 3.74(2H, s), 10.58(1H, s),14.36(1H, s); F+: 408 142 6-CH₂-(4-cHex-Pipera) 6 N1: 0.97-1.27(6H, m),3.51(2H, s), 10.57(1H, s), 14.38(1H, s); F+: 441

TABLE 12 143

6 N1: 2.09(6H, s), 3.51(2H, s), 10.57(1H, s), 14.38 (1H, s); F−: 442 1446-(CH₂)₂CONHOCH₂-cPr 8 F+: 402 145 6-CONH(CH₂)₂-Morp 8 F+: 417 1466-CONHCH₂CO₂Et 8 F−: 388 147 6-CONH(CH₂)₂-Py4 8 F+: 409 148 6-CO-Pim 8N1: 2.21(3H, s), 2.30-2.40(4H, m), 3.36-3.75(4H, m), 10.63(1H, s),14.32(1H, s); F+: 387 149 6-CONHMe 8 N1: 2.81(3H, d), 8.51(1H, q),10.64(1H, s), 14.31(1H, s); F+: 318 150

8 N1: 2.25(3H×½, s), 2.29(3H×½, s), 10.62(1H, s), 14.32(1H, s); F+: 401151 6-CON(Me)(CH₂)₂NEt₂ 8 N1: 0.70-1.10(6H, m), 2.20-2.70(6H, m),3.31(3H, s), 3.28-3.56(2H, m), 10.62(1H, s), 14.32(1H, s) 1526-CO(4-cPr-Pipera) 8 N1: 0.32-0.36(1H, m), 0.42-0.46(1H, m),1.64-1.70(1H, m), 2.52-2.62(4H, m), 3.30-3.65(4H, m), 10.63(1H, s),14.32(1H, s); F+: 413 153 6-CO(4-Et-Pipera) 8 N1: 1.01(3H, t), 2.36(2H,q), 2.30-2.50(4H, m), 3.30-3.70(4H, m), 10.63(1H, s), 14.32(1H, s); F+:401 154 6-CON(Me)OMe 8 N1: 3.31(3H, s), 3.60(3H, s), 10.64(1H, s),14.31(1H, s); F+: 348 155 6-CO(4-NMe₂-Pip1) 8 N1: 1.3-1.5(2H, m),1.6-2.0(2H, m), 2.21(6H, s), 2.3-2.5(1H, m), 3.6-3.9(1H, m), 4.2-4.6(1H,m), 10.63(1H, s), 14.32(1H, s); F−: 413 156

8 N1: 2.87(2H, t), 3.55(2H, q), 7.29(2H, d), 8.12(2H, d), 8.62(1H, t),10.65(1H, s), 14.30(1H, s); F+: 425 157 6-CO(4-Boc-Pipera) HCl 8 F+: 473158 6-CO(4-CO₂Et-Pip1) 8 F+: 444 159 4-CONH(CH₂)₂-Morp 8 N1: 2.56(2H,t), 3.30(4H, s), 3.49(2H, q), 3.64(4H, t), 8.92(1H, t), 10.66(1H, s),14.21(1H, s); F+: 417 160 4-CONH(CH₂)₂NEt₂ 8 N1: 1.02(6H, t), 2.58(4H,q), 2.65(2H, t), 8.88 (1H, t), 10.66(1H, s), 14.22(1H, s); F+: 403 161

8 F+: 417 162 4-CON(Me)(CH₂)₂NEt₂ HCl 8 F+: 417 163 4-CONH(CH₂)₃-Morp 8N1: 1.77(2H, qui), 2.36-2.43(6H, m), 3.39(2H, q), 3.58 (4H, t), 8.99(1H,t), 10.66(1H, s), 14.23(1H, s); F+: 431 164

8 N1: 1.42-1.77(4H, m), 2.27(3H, s), 9.00(1H, br), 10.67(1H, s),14.21(1H, s); F+: 415 165 4-CONH(4-NH₂-cHex) 8 F+: 401 1664-CO(4-Pip1-Pip1) HCl 8 F+: 455 167 4-CONH(3-NH₂-cHex) 8 F+: 401

TABLE 13 168

8 F: 400 169 4-CONHCH₂-Pyra 8 N1: 4.7-4.8(2H, m), 8.61(1H, s), 8.63(1H,s), 8.79(1H, s), 9.54-9.70(1H, m), 10.67(1H, s), 14.20(1H, s); F+: 396170 4-CONH-Pyrim5 8 N1: 9.02(1H, s), 9.20(2H, s), 10.70(1H, s),11.33(1H, s), 14.29(1H, s); F+: 382 171 7-CONH(CH₂)₂-Morp 8 F+: 417 1727-CON(Me)(CH₂)₂-NEt₂ 8 F+: 417 173 7-CO-Pim 8 F+: 387 174

8 N1: 1.23(9H×½, s), 1.34(9H×½, s), 7.22(1H, brs), 10.63(1H, s),14.32(1H, s); F+: 473 175

8 N1: 1.63-1.71(1H, m), 1.81-1.94(2H, m), 1.95-2.05(1H, m), 3.44(2H,td), 3.69(1H, q), 3.83(1H, q), 4.07(1H, qui), 9.07(1H, t), 10.65(1H, s),14.21(1H, s); F+: 388 176

8 N1: 2.45-2.52(4H, m), 3.32(2H, s), 3.65-3.90(4H, m), 10.63(1H, s),14.32(1H, s); F−: 384 177 5-NH₂ 10 F: 275 178 6-OH 10 F: 276 1796-O(CH₂)₂(4-CO₂H-Pip1) HCl 23 F+: 432 180 6-O(CH₂)₃CO₂H 23 F+: 363 1816-OCH₂CO₂H 23 F−: 333 182 6-CONHCH₂CO₂H 23 F−: 360 183 7-(CH₂)₂CO₂H 23F+: 333 184 6-OCH₂-Pip4 12 F+: 374 185

12 N1: 3.87(2H, s), 10.58(1H, s), 14.42(1H, s) 186

HCl 12 F+: 373 187 4-CH₂OH 14 F+: 291 188 5-NHCONH—CH₂CO₂Bu 16 F+: 433366 6-CH₂NHCH₂(2-NH₂-Py4) 5 N1: 2.75(1H.brs), 3.57(2H, s), 3.75(2H, s),5.79(2H, s), 6.46(1H, s), 6.49(1H, d), 7.82(1H, d), 10.57(1H, s),14.39(1H, s); F+: 396 367

5 N1: 3.88(2H, brs), 10.59(1H, s), 14.36(1H, s); F−: 420 3686-CO(4-Pim-Pip1) 6 N1: 2.14(3H, s), 10.63(1H, s), 14.32(1H, s); F+: 470369

8 N1: 1.55(2H, qui), 2.11(6H, s), 10.63(1H, s), 14.32(1H, s); F+: 458370 6-CO(4-CO₂H-Pip1) 23 N1: 10.62(1H, s), 12.30(1H, brs), 14.30(1H, s);F+: 416 371 6-CO(4-CO₂Et-Pip1) 8 F+: 444

TABLE 14 (I)

Ex (R²)m Sy Dat 17 6-COOEt — F+: 333 18 5-NMe₂ — F+: 304 19 6-OMe — F−:279 20 6-C(Me)═N—OMe — F+: 332 21 6-Ac — F+: 303 22 5-COOH — F+: 305 235-(CH₂)₃COOH — F+: 347 24 5-OH — F+: 277 25 6-COOH — F−: 303 26 6-Pyrr2— F+: 326 27 5-(2-Me-Thia4) — F+: 358 28 5-CO(CH₂)₃OH — F+: 347 1896-CONEt₂ 17 F+: 360 190 6-CONH(CH2)2NEt2 17 F+: 403 191 6-CN 17 F+: 286192 6-CH₂NEt₂ 17 F+: 346 193 6-CHO 17 F+: 289 194 6-COO(CH₂)₂NMe₂ 17 F+:404 195 6-COOBn 17 F+: 395 196 5-OCH₂COOEt 17 F+: 363 197 6-CONH₂ 17 F+:304 198 5-Cl-6-CF₃ 17 F+: 363 199 6-CONHEt 17 F+: 332 200 5-Cl-6-COOEt17 F+: 367 201 5-Me 17 F: 274 202 5-OCH₂Py2 17 F+: 368 203 6-CF₃ 17 F:328 204 5-F-6-COOEt 17 F+: 351 205 6-Br 17 F: 338, 340 206 6-COPr 17 F+:331 207 5-OMe 17 F−: 289 208 6-Thia4 17 F+: 344 209 6-F 17 F−: 277 2105-O(CH₂)₂NMe₂ 17 F+: 348 211 7-F 17 F: 278 212 5-O(CH₂)₃NMe₂ 17 F+: 362213 5-F 17 F−: 277 214 5-OCH₂(1-Me-Pip2) 17 F+: 388 215 6-SO₂Me 17 F+:339 216 5-O(1-Me-Pip3) 17 F+: 374 217 6-Cl 17 F: 294 218 6-CONHOCH₂cPr17 F+: 374 219 4-Cl 17 F−: 293 220 5-OMe-6-COOEt 17 F+: 363 221 5-OBn 17F+: 367 222 5-Me-6-COOEt 17 F+: 347 223 5-CF₃ 17 F−: 327 2245-CH₂NEt₂-6-COOEt 17 F+: 418 225

17 F+: 342 226

17 F+: 344 227

17 F+: 330 228

17 F+: 344 229

17 F+: 358 230

17 F+: 342 231 6-CH═N—OMe 17 F+: 318 232 6-CH₂CN 17 F−: 298 2335-O(CH₂)₂Br 17 F+: 383, 385 234 5-Morp 17 F+: 346 235 5-Im1 18 F+: 327236 5-NH(CH₂)₂NEt₂ 18 F+: 375 237 5-NHBn 18 F−: 364 238 5-COCH₂Morp 19F+: 338 239 5-COOEt 19 F+: 333 240 5-COMe 19 F+: 303

TABLE 15 241 6-Me 19 F−:273 242 6-F₂ 19 F−:295 243 5-CN 19 E:285 244(Thie3) 19 F+:343 245 5-(CH₂)₂-Morp 19 F+:374 246 SO₂NH₂ 19 F+:340 2476-(2-OMe-Ph) 19 F:366 248 O(CH₂)₂NEt₂ 19 F+:376 249 4-O(CH₂)₂NEt₂ 19F+:376 250 O(CH₂)₂NEt₂ 19 F+:376 251 5-(CH₂)₃CO₂Et 19 F+:375 2525-CONH(CH₂)₂NEt₂ 19 F−:401 253 5-(CH₂)₄CO₂Me 19 F+:375 2545-CO(CH₂)₂CO₂Et 19 F+:389 255 6-Fu3 19 F+:327 256 CO(CH₂)₃CO₂Me 19F−:387 257 6-(1-Boc-Pyrr2) 19 F+:426 258 5-NHAc-6-Cl 19 F−:350 2596-CH₂OEt 19 F+:319 260 4-OBn 19 F+:367 261 5-COCH₂Cl 19 F+:337 2625-CO(CH₂)₂Cl 19 F+:351 263 5-CO(CH₂)₃Cl 19 F+:365 264 5-(CH₂)₄Cl 19F+:351 265 6-OCOMe 19 F+:317 266 7-OCOMe 19 F+:317 267 5-COCH₂-Im1 4F+:369 268 5-COCH₂NMe₂ 4 F+:344 269 5-COCH₂-Thiom 4 F+:404 2705-COCH₂(4-OH-Pip1) 4 F+:402 271 5-CO(CH₂)₂-Morp 4 F+:402 2725-COCH₂(3-OH-Pip1) 4 F+:402 273 5-CO(CH₂)₂NMe₂ 4 F+:360 2745-CO(CH₂)₂-Im1 4 F:383 275 5-(CH₂)₄-Im1 4 F−:381 276 5-CO(CH₂)₂N(Me)Bn 4F:436 277 5-COCH₂NEt₂ 4 F+:374 278 6-CONH(CH₂)₂OAc 8 F+:390 2795-CO(CH₂)₃COOH 23 F+:375 280 5-OCH₂COOH 23 F+:335 281 4-OH 24 E:276 2826-OH 23 F+:277 372 6-(CH₂)₃NMe₂ 10 F+:346 373 6-CH═N-O(CH₂)₂NMe₂ 17F+:375

TABLE 16 Ex (R²)m Sal Sy Dat 283 5-Cl 1 N2: 10.72(1H, s), 14.51(1H, s);F+: 295 284 5-NO₂ HCl 1 N1: 11.30(1H, s), 14.45(1H, s) 285 5-Br HCl 1N1: 10.75(1H, s), 14.51(1H, s); F+: 339, 401 286 5-O(CH₂)₂NEt₂ 19 N1:1.01(6H, brs), 2.60(4H, brs), 2.80(2H, brs), 4.07(2H, brs), 10.39(1H,s), 14.46(1H, s); F+: 376 287 6-(2-Me-Thia4) 17 N1: 2.72(3H, s),10.69(1H, s), 14.33(1H, s) 288

17 N1: 7.32(1H, s), 8.14(1H, s)10.83(1H, s), 14.51(1H, s); F+: 328 289

17 N1: 0.94(3H, t), 1.45-1.67(2H.m), 3.99(1H, t), 4.10-4.20(1H, m),4.45(1H, t), 10.78(1H, s), 14.53(1H, s); F+: 358 290 6-CH═N—OBn 29 N1:5.15(2H, s), 8.27(1H, s), 10.71(1H, s), 14.44(1H, s); F+: 394 2916-CH═N—OCH₂Py4 29 N1: 5.47(2H, s), 10.75(1H, s), 14.44(1H, s); F+: 395292 5-COOAc 19 N1: 2.41(3H, s), 10.97(1H, s), 14.41(1H, s)

TABLE 17 (I)

Ex (R²)m Sal Sy Dat 29 6-CH═N—OEt HCl — N1: 1.25(3H, t), 4.13(2H, q),8.17(1H, s), 10.68(1H, s), 14.53(1H, s); F+: 461 293 5-Cl 4 N1:2.48-2.52(4H, m), 2.74(2H, t), 3.59(4H, t), 4.18(2H, t), 10.66(1H, s),14.61(1H, s); F+: 424 294 6-COOEt 17 N1: 1.33(3H, t), 4.29(2H, q),10.76(1H, s), 14.76(1H, s); F+: 462 295 6-CN 17 N1: 2.75(2H, m),3.2-3.3(4H, m), 4.20(2H, t), 10.90(1H, s), 14.83(1H, s); F+: 415 2966-CF₃ 17 N1: 2.7-2.8(2H, m), 3.5-3.6(4H, m), 4.1-4.2(2H, m), 10.85(1H,s), 14.72(1H, s); F+: 458 297

17 N1: 3.93(2H, t), 4.34(2H, t), 10.72(1H, s), 14.64(1H, s); F+: 459 2985-Cl-6-COOEt 17 N1: 1.32(3H, t), 4.29(2H, q), 10.83(1H, s), 14.79(1H,s); F+: 496 299 5-F-6-COOEt 17 N1: 1.31(3H, t), 4.28(2H, q), 10.73(1H,s), 14.84(1H, s); F+: 480 300 5-OMe-6-COOEt 17 F+: 492 301 5-Me-6-COOEt17 N1: 1.32(3H, t), 2.61(3H, s), 4.26(2H, q), 10.59(1H, s), 14.70(1H,s); F+: 476 302 5-Me-6-COOMe 17 N1: 2.61(3H, s), 3.79(3H, s), 10.63(1H,s), 14.71(1H, s); F+: 462 303 5-Me-6-COOiPr 17 F+: 490 304 5-Me-6-COOPr17 N1: 0.99(3H, t), 1.67-1.78(2H, m), 2.62(3H, s), 10.59(1H, s),14.71(1H, s); F+: 490 305 5-Me-6-COOBu 17 F+: 504 306 5-Me-6-(CH═N—OMe)17 N1: 2.42(3H, s), 3.82(3H, s), 8.37(1H, s), 10.50(1H, s), 14.50(1H,s); F+: 461 307 6-CH═N—OMe 29 N1: 2.73(2H, t), 3.87(3H, s), 4.17(2H, t),8.17(1H, s), 10.67(1H, s), 14.54(1H, s); F+: 447 308 6-CH═N—OiBu HCl 29F+: 489 309 6-CH═N—OBn HCl 29 N1: 5.15(2H, s), 8.26(1H, s), 10.68(1H,s), 14.54(1H, s); F+: 523 310 6-F 4 N1: 2.73(2H, t), 3.5-3.6(4H, m),4.16(2H, t), 10.66(1H, s), 14.32(1H, s); F+: 408 311 5-F 4 N1:2.7-2.8(2H, m), 3.5-3.6(4H, m), 4.18(2H, t), 10.53(1H, s), 14.62(1H, s);F+: 408 312 6-Cl 4 N1: 2.74(2H, t), 3.2-3.4(4H, m), 3.5-3.6(4H, m),4.18(2H, t), 10.67(1H, s), 14.44(1H, s); F+: 424 313 6-COOH 23 F+: 434

TABLE 18 (I)

Ex (R²)m (R¹)n Sal Sy Dat 314 5-Me-6-CO₂Et 6-O(CH₂)₂Br 19 F+: 469, 471315 6-F 6-(CH₂)₃Br 19 F: 399, 401 316 6-F 6-CHO 19 N1: 9.97(1H, s),10.83(1H, s), 14.12(1H, s) 317 5-Me-6-CO₂Et 6-CHO 19 F+: 375 3185-Me-6-CO₂Et 6-(CH₂)₃Br 19 F+: 467, 469 319 6-CH═NOMe 6-CHO 19 F+: 346320 6-CH═NOMe 6-(CH₂)₃Br 19 F+: 438, 440 321 5-Me-6-CO₂Et 6-CO₂H 19 N1:1.32(3H, t), 2.60(3H, s), 4.26(2H, q), 10.72(1H, s), 14.54(1H, s); F+:391 322 5-Cl 6-O(CH₂)₂Br 1 F: 418 323 6-F 6-O(CH₂)₂Br 1 F: 400, 402 3245-F 6-O(CH₂)₂Br 1 F: 400, 402 325 6-Cl 6-O(CH₂)₂Br 1 F: 416, 418 3265-NO₂ 6-O(CH₂)₂Br 1 E: 427, 429 327 5-CN 6-O(CH₂)₂Br 1 F: 407, 409 3285,6-F2 6-O(CH₂)₂Br 1 F+: 419, 421 329 5-F 6-(CH₂)₂CO₂H 1 F+: 351 330 6-F6-O(CH₂)₂Cl 1 N1: 4.00(2H, t), 4.25(2H, t), 10.68(1H, s), 14.42(1H, s)331 6-Cl 6-O(CH₂)₂Cl 1 F−: 355 332 5-Me-6-CO₂Et 6-O(CH₂)₂Pim 2HCl 4 N1:1.32(3H, t), 2.61(3H, s), 4.26(2H, q), 10.62(1H, s), 14.69(1H, s); F+:489 333 6-F 6-O(CH₂)₂NEt₂ 4 N1: 1.01(6H, t), 2.59(4H, q), 2.7-2.8(2H,m), 4.09(2H, t), 10.65(1H, s), 14.32(1H, s); F+: 394 334 6-F6-O(CH₂)₂Pim 4 N1: 2.17(3H, s), 2.3-2.5(4H, m), 2.73(2H, t), 4.15(2H,t), 10.65(1H, s), 14.32(1H, s); F+: 421 335 5-F 6-O(CH₂)₂NEt₂ 4 N1:0.99(6H, t), 2.57(4H, q), 2.82(2H, t), 4.11(2H, t), 10.54(1H, s),14.63(1H, s); F+: 394 336 5-F 6-O(CH₂)₂Pim 4 N1: 2.15(3H, s),2.3-2.4(2H, m), 2.73(2H, t), 4.15(2H, t), 10.54(1H, s), 14.62(1H, s);F+: 421 337 6-Cl 6-O(CH₂)₂NEt₂ 4 N1: 1.00(6H, t), 2.5-2.7(4H, m),2.8-2.9(2H, m), 4.11(2H, t), 10.67(1H, s), 14.45(1H, s); F+: 410

TABLE 19 338 6-Cl 6-O(CH₂)₂Pim 4 N1:2.17(3H, s), 2.3-2.5(4H, m),2.73(2H, t), 4.17(2H, t), 10.68(1H, s), 14.44(1H, s) ; F+:437 339 5-NO₂6-O(CH₂)₂Morp 4 F+:435 340 5-CN 6-O(CH₂)₂Morp 4 F+:415 341 5,6-F₂6-O(CH₂)₂Morp 4 N1:2.73(2H, t), 3.59(4H, t), 4.17(2H, t), 10.63(1H, s),14.50(1H, s):F+:426 342 5-Me-6-CO₂Et 6-O(CH₂)₂NEt₂ HCl 4 N1:1.27(6H,t),1.32(3H, t), 2.61(3H,s), 4.26(2H,q), 10.62(1H,s), 14.70(1H,s) ; F+:462343 6-F 6-(CH₂)₃NEt₂ 4 N1:0.93(6H, t), 1.6-1.8(2H, m), 2.3-2.5(6H, m),2.67(2H, t), 10.69(1H, s), 14.24(1H, s) ; F+:392 344 6-F 6-(CH₂)₃Morp 4N1:1.7-1.9(2H, m), 2.2-2.4(6H, m), 2.6-2.7(2H, m), 3.4-3.6(2H, m),10.69(1H, s), 14.23(1H, s) ; F−:404 345 6-F 6-(CH₂)₃Pim 4 N1:1.7-1.8(2H,m), 2.15(3H, s), 2.2-2.4(8H, m), 2.67(2H, t), 10.68(1H, s), 14.23(1H, s); F−:417 346 5-Me-6-CO₂Et 6-(CH₂)₃Morp 4 N1:1.32(3H, t), 2.61(3H, s),4.26(2H, q), 10.63(1H, s), 14.61(1H, s) ; F+:474 347 6-CH═NOMe6-(CH₂)₃Morp 4 N1:3.87(3H, s), 8.18(1H, s), 10.70(1H, s), 14.46(1H, s) ;F+:445 348 5-Me-6-CO₂Et 6-(CH₂)₃Pim 4 N1:1.32(3H, t), 2.15(3H, s),2.61(3H, s), 4.26(2H, q), 10.62(1H, s), 14.62(1H, s) ; F+:487 3496-CH═NOMe 6-(CH₂)₃Pim 4 N1:2.15(3H, s), 3.87(3H, s), 8.18(1H, s),10.70(1H, s), 14.46(1H, s) ; F+:458 350 6-F 6-CH₂Pim 5 N1:2.15(3H, s),2.2-2.6(8H, m), 3.32(2H, s), 10.71(1H, s), 14.24(1H, s) ; F+:391 3515-Me-6-CO₂Et 6-CH₂Pim 5 N1:1.33(3H, t), 2.62(3H, s), 2.87(3H, s),4.26(2H, s), 4.29(2H, q), 10.70(1H, s), 14.55(1H, s) ; F+:459 3526-CH═NOMe 6-CH₂Pim 5 N1:3.87(3H, s), 8.18(1H, s), 10.72(1H, s),14.46(1H, s) ; F+:429 353 5-Me-6-CO₂Et 6-COPim 8 N1:1.32(3H, t),2.24(3H, s), 2.62(3H, s), 4.26(2H, q), 10.70(1H, s), 14.56(1H, s) ;F+:473

TABLE 20 Ex Str Sy Dat 30

— F+: 319 354

18 F+: 389 355

17 F+: 262 356

18 F+: 306 357

30 F+: 277 358

18 F+: 446, 448 359

30 F+: 348 360

19 F+: 262 361

17 F+: 297 362

19 F+: 262 363

18 F+: 377 364

19 F+: 262 365

18 F+: 348 374

19 F+: 380, 382 375

29 N1: 5.22(2H, s), 8.35(1H, s), 10.70(1H, s), 14.44(1H, s); F+: 395 376

29 N1: 5.19(2H, s), 8.28(1H, s), 10.71(1H, s), 14.45(1H, s); F+: 395 377

17 N1: 2.18(6H, s), 3.18(2H, d), 5.62(1H, dt), 6.52(1H, d), 10.60(1H,s), 14.30(1H, s); F+: 344 378

17 N1: 2.23(6H, s), 3.09(2H, d), 6.13(1H, dt), 6.54(1H, d), 10.60(1H,s), 14.28(1H, s); F+: 344 379

5 N1: 2.43-2.50(1H, m), 2.98(1H, qui), 3.79(2H, s), 10.56 (1H, s),14.38(1H, s); F+: 397

TABLE 21 (I)

Co (R¹)n 1 5-Me-6-O(CH₂)₃CO₂H 2 5-NHSO₂(CH₂)₂-Morp 3 5-NHCOCH₂-Morp 45-NH(CH₂)₂OMe 5 5-C≡C—CH₂NEt₂ 6 5-CH₂CH₂CO₂H 7 4-Cl-6-O(CH₂)₃CO₂H 86-O(CH₂)₂NHSO₂Me 9 6-N(Me)CO-Pim 10 6-CH₂(4-CH₂OC₂H-Pip1) 116-CH₂(4-iPr-Pipera) 12 6-CH₂(4-iBu-Pipera) 13 6-CH₂NHCH₂(4-Me-Py3) 14

15

16 4-CONH(CH₂)₂OMe-6-CH₂-Pim 17 5-CN-6-O(CH₂)₃CO₂H 185-CH═NOMe-6-O(CH₂)₃CO₂H 19 6-CH═CHCO₂H 20 5-CH₂OH-6-O(CH₂)₃CO₂H 216-NHSO₂(CH₂)₂-Morp 22 6-NH(CH₂)₂OMe 23 6-CH═CHCH₂NEt₂ 245-CONMe₂-6-O(CH₂)₃CO₂H 25 6-CON(CH₂CO₂H)₂ 26 6-CO(4-(CH₂)₂CO₂H-Pip1) 276-CH₂(4-CH₂C(CH₃)₃-Pipera) 28 6-CH₂NHCH₂(4-CN-cHex) 29

30 6-O(CH₂)₂(4-(CH₂)₂CO₂H-Pip1) 31 5-NHCO-Pim 32 5-CH₂-Pim 335-(CH₂)₃-Pim 34 5-CO-Pim 35 6-(CH₂)₂-Pim 36 6-NHCO-Pim 37 6-SO₂-Pim 386-C≡C—CO₂H 39 6-C≡C—CH₂NEt₂ 40 6-(4-CO₂H-Pip1) 41 6-CH₂(4-CN-Pip1) 426-(CH₂)₃-Tet 43 6-N(CH₂CO₂H)₂ 44

TABLE 22 (I)

Co (R²)m (R¹)n 45 6-F 5-CH₂OH-6-O(CH₂)₃CO₂H 46 6-CH═N—OMe5-CH₂OH-6-O(CH₂)₃CO₂H 47 5-Me-6-CO₂Et 6-(CH₂)₂CO₂H 48 5-Me-6-CO₂Et6-O(CH₂)₃CO₂H 49 6-CH═N—OMe 6-(CH₂)₂CO₂H 50 6-CH═N—OMe 6-O(CH₂)₃CO₂H 516-CH═N—OCH₂-Tet −(n = 0) 52 6-CH═N—OCH₂-Im2 −(n = 0) 536-CH═N—OCH₂(6-NMe₂-Py2) −(n = 0) 54 6-CH═N—OCH₂(6-Pim-Py2) −(n = 0) 556-CH═N—OCH₂CO₂H −(n = 0)

1. A 3-quinolin-2(1H)-ylideneindolin-2-one derivative represented by thefollowing general formula (I) or a salt thereof,

(symbols in the formula have the following meanings; A, B, E, G and J:the same or different from one another and each represents N atom or Catom, R¹ and R²: the same or different from each other and eachrepresents a lower alkyl, a lower alkenyl, a lower alkynyl, R^(a),X—(C₁₋₈ alkylene which may be substituted by OR^(b))—R^(a), X—(C₁₋₈alkenylene)-R^(a) or X—(C₁₋₈ alkynylene)-R^(a), with the proviso thateach of R¹ and R² does not substitute to the ring nitrogen atom, X: O,CO, COO, OCO, S, SO, SO₂, NR^(b), NR^(b)SO₂, SO₂NR^(b), CONR^(b),NR^(b)CO, NR^(b)CONR^(c), NR^(b)COO, OCONR^(b) or a bond, R^(a): ahalogeno lower alkyl, a halogen, NO₂, CN, OR^(b), O-(loweralkylene)-NR^(b)R^(c), COOR^(b), COR^(b), CONR^(b)R^(c), NR^(b)R^(c),NR^(d)-(lower alkylene)-NR^(b)R^(c), NR^(d)-(lower alkylene)-OR^(b),N(lower alkylene-NR^(b)R^(c))₂, NR^(c)COR^(b), NR^(d)CONR^(b)R^(c),SR^(b), SO-lower alkyl, SO₂-lower alkyl, SO₂RIN, SO₂-(loweralkylene)-RIN, RIN, SO₂NR^(b)R^(c), NR^(c)SO₂R^(b), NR^(c)COOR^(b),OCO—NR^(b)R^(c), OCO—R^(b), NR^(d)-(lower alkylene)-COOR^(b), N(loweralkylene-COOR^(b))₂, CONR^(b)—OR^(c), CONR^(d)-(loweralkylene)-COOR^(b), CON(lower alkylene-COOR^(b))₂, CR^(d)═N—O—R^(c),CR^(d)═N—O-(lower alkylene)-COOR^(b) or CR^(d)═N—O-(loweralkylene)-NR^(b)R^(c), R^(b), R^(c) and R^(d): the same or differentfrom one another and each represents H, a lower alkyl, a loweralkylene-RIN or RIN, RIN: a saturated heterocyclic ring which may haveone or more substituents, a cycloalkyl which may have one or moresubstituents, an aryl which may have one or more substituents or aheteroaryl which may have one or more substituents, and n and m: thesame or different from each other and each is 0 or an integer of from 1to 4, with the proviso that they are not 0 at the same time when all ofA, B, E, G and J are C atom).
 2. The3-quinolin-2(1H)-ylideneindolin-2-one derivative or a salt thereofaccording to claim 1, wherein all of A, B, E, G and J are C atom.
 3. The3-quinolin-2(1H)-ylideneindolin-2-one derivative or a salt thereofaccording to claim 2, wherein m is 0, 1 or 2; R² is a lower alkyl,R^(a2) or X²—(C₁₋₈ alkylene)-R^(a2); X² is O, CO, COO, NR^(b), CONR^(b)or a bond; and R^(a2) is a halogeno lower alkyl, a halogen, NO₂, CN,OR^(b), COOR^(b), COR^(b), CONR^(b)R^(c), NR^(c)COR^(b), NR^(b)R^(c),SO₂-lower alkyl, RIN, SO₂NR^(b)R^(c), OCO—R^(b), CONR^(b)—OR^(c),CR^(d)═N—OR^(c) or CR^(d)═N—O-(lower alkylene)-NR^(b)R^(c).
 4. The3-quinolin-2(1H)-ylideneindolin-2-one derivative or a salt thereofaccording to claim 3, wherein n is 0, 1 or 2; R¹ is a lower alkyl,R^(a1) or X¹—(C₁₋₈ alkylene which may be substituted by OR^(b))—R^(a1);X¹ is O, CONR^(b), NR^(b)CO, NR^(b)CONR^(c) or a bond; and R^(a1) is ahalogen, NO₂, CN, OR^(b), COOR^(b), COR^(b), CONR^(b)R^(c), NR^(b)R^(c),NR^(d)-(lower alkylene)-NR^(b)R^(c), NR^(d)-(lower alkylene)-OR^(b),NR^(d)CONR^(b)R^(c), RIN, OCO—R^(b), NR^(d)-(lower alkylene)-COOR^(b) orCONR^(b)—OR^(c).
 5. A pharmaceutical composition which comprise a3-quinolin-2(1H)-ylideneindolin-2-one derivative represented by thefollowing general formula (I′) or a salt thereof and a pharmaceuticallyacceptable carrier,

(symbols in the formula have the following meanings; A, B, E, G and J:the same or different from one another and each represents N atom or Catom, R¹ and R²: the same or different from each other and eachrepresents a lower alkyl, a lower alkenyl, a lower alkynyl, R^(a),X—(C₁₋₈ alkylene which may be substituted by OR^(b))—R^(a), X—(C₁₋₈alkenylene)-R^(a) or X—(C₁₋₈ alkynylene)-R^(a), with the proviso thateach of R¹ and R² does not substitute to the ring nitrogen atom, X: O,CO, COO, OCO, S, SO, SO₂, NR^(b), NR^(b)SO₂, SO₂NR^(b), CONR^(b),NR^(b)CO, NR^(b)CONR^(c), NR^(b)COO, OCONR^(b) or a bond, R^(a): ahalogeno lower alkyl, a halogen, NO₂, CN, OR^(b), O-(loweralkylene)-NR^(b)R^(c), COOR^(b), COR^(b), CONR^(b)R^(c), NR^(b)R^(c),NR^(d)-(lower alkylene)-NR^(b)R^(c), NR^(d)-(lower alkylene)-OR^(b),N(lower alkylene-NR^(b)R^(c))₂, NR^(c)COR^(b), NR^(d)CONR^(b)R^(c),SR^(b), SO-lower alkyl, SO₂-lower alkyl, SO₂RIN, SO₂-(loweralkylene)-RIN, RIN, SO₂NR^(b)R^(c), NR^(c)SO₂R^(b), NR^(c)COOR^(b),OCO—NR^(b)R^(c), OCO—R^(b), NR^(d)-(lower alkylene)-COOR^(b), N(loweralkylene-COOR^(b))₂, CONR^(b)—OR^(c), CONR^(d)-(loweralkylene)-COOR^(b), CON(lower alkylene-COOR^(b))₂, CR^(d)═N—O—R^(c),CR^(d)═N—O-(lower alkylene)-COOR^(b) or CR^(d)═N—O-(loweralkylene)-NR^(b)R^(c), R^(b), R^(c) and R^(d): the same or differentfrom one another and each represents H, a lower alkyl, a loweralkylene-RIN or RIN, RIN: a saturated heterocyclic ring which may haveone or more substituents, a cycloalkyl which may have one or moresubstituents, an aryl which may have one or more substituents or aheteroaryl which may have one or more substituents, and n and m: thesame or different from each other and each is 0 or an integer of from 1to 4).
 6. The pharmaceutical composition according to claim 5, which isa vascular endothelial growth factor inhibitor.
 7. The pharmaceuticalcomposition according to claim 5, which is an angiogenesis inhibitor. 8.The pharmaceutical composition according to claim 5, which is ananti-tumor agent.